1925

"The key to every biological problem must finally be sought in the cell." Edmund Beecher Wilson (3027).

“When we consider what religion is for mankind, and what science is, it is no exaggeration to say that the future course of history depends upon the decision of this generation as to the relations between them.” Alfred North Whitehead (2974).

“Almost all new ideas have a certain aspect of foolishness when they are first proposed.” Alfred North Whitehead (2974).

Richard Adolf Zsigmondy (AT-DE) received the Nobel Prize in Chemistry for his demonstration of the heterogeneous nature of colloid solutions and for the methods he used, which have since become fundamental in modern colloid chemistry. He developed a dark field ultramicroscope could detect particles with diameters below the wavelengths of visible light.

Gottfried Koller (DE), Earle B. Perkins (US), Theodore Snook (US), and Benjamin Kropp (US) found that there is produced in the eyestalks of crustaceans a hormone which, when carried in the blood stream, is effective in inducing chromatophore changes. Koller named this hormone contractin (1484-1486, 2069-2071).

Edouard Chatton (FR) first used the terms prokaryote and eukaryote in his 1925 paper when he suggested that the most significant taxonomic distinction among life forms today is not between plants and animals but between cells with nuclei, eukaryotes, and cells without them, prokaryotes. Pro means before and eu means true, karyote refers to a nut or kernel (445, 446).“Protozoologists agree today in considering the flagellated autotrophs the most primitive of the Protozoa possessing a true nucleus, Eukaryotes (a group which also includes the plants and the Metazoans), because they alone have the power to completely synthesize their protoplasm from a mineral milieu. Heterotrophic organisms are therefore dependent on them for their existence as well as on chemotrophic Prokaryotes and autotrophs (nitrifying and sulphurous bacteria, Cyanophyceae.” This is a translation by Jan Sapp (CA) from the 1938 reference (2365).

Eukaryotes are now placed in the domain Eucarya while prokaryotes are placed in either the domain Bacteria or Archaea.

Ellsworth C. Dougherty (US) proposed the prokaryotic-eukaryotic dichotomy. He used the words eukaryon (Greek: true kernel) for the nucleus of “higher organisms” and prokaryon (Greek: before kernel) for the moneran nucleus. (727).

Roger Yate Stanier (CA) and Cornelis Bernardus Kees van Niel (NL-US) later defined bacteria by conceptualizing two new biological entities, "prokaryotes" and "eukaryotes." They argued that the cells of all living things were either prokaryotic or eukaryotic, depending on their pattern of cellular organization. They defined eukaryotes as cells containing membrane-bound structures called organelles, the most important of which was the nucleus. By this definition, all cells of multi-cellular plants and animals were eukaryotes. Cells that lacked membrane-bound cell nuclei, like bacteria and blue-green algae, were designated prokaryotes. The term prokaryote implicitly elevated bacteria to equivalent biological status with all other organisms, to be known as eukaryotes (2605). This represents the resurrection and embellishment of an idea first conceived by Edouard Chatton (FR).

Robert George Everitt Murray (CA) proposed Procaryotae as a taxon “at the highest level” and described it as “a kingdom of microbes…characterized by the possession of nucleoplasm devoid of basic protein and not bounded from cytoplasm by a nuclear membrane.” He suggested Eucaryotae as a possible taxon at the same level to include other protists, plants, and animals (1951).

Agnes Robertson Arber (GB) authored Monocotyledons; a Morphological Study, which developed the thesis, first suggested by A.P. de Candolle, that the monocot leaf is derived from a dicot petiole (phyllode theory) (68).

Emil-Karl Frey (DE) observed in 1925 a considerable reduction in arterial blood pressure when he injected human urine into dogs. Unlike many other contemporary scientists he did not attribute this effect to a toxic action of urine, but rather as the specific activity of an unknown substance with potential biological functions (950, 951).

Heinrich Kraut (DE), Emil-Karl Frey (DE) and Eugen Werle (DE) reasoned that, “It is a substance that probably originates from several organs, is eliminated by the kidneys and has a pronounced cardioactive and vasoactive effect: a substance that is assigned the role of a hormone in the organism”. This F-substance was then called kallikrein, since it was considered to have originated in the pancreas (Greek synonym: kallikreas) (1505).

Eugen Werle (DE), W. Götze (DE), A. Keppler (DE), and M. Grunz (DE) discovered kinins when they gave evidence that a smooth muscle stimulating substance KLK (tissue kallikrein) is a proteolytic enzyme, which liberates the biologically highly active basic polypeptide kallidin (KD) from the plasma protein, kallidinogen or kininogen (2949, 2950). Its name was later changed to kallidin and that of the precursor to kallidinogen. This work laid the foundation for understanding the system that we refer to today as the kallikrein-kinin system (cascade).

George Edward Briggs (GB) and John Burdon Sanderson Haldane (GB-IN) made important refinements in the theory of enzyme kinetics with their steady-state derivation of the single-substrate enzyme saturation curve (299).

Earl Perry Cark (US) and James Bertram Collip (CA) reported an important improvement in the methodology for the determination of blood serum calcium (463).

Cyrus Hartwell Fiske (US) and Yellapragada Subbarow (US) developed a colorimetric method useful for the detection of phosphorus in organic material (909).

Evert Gorter (NL) and Francois Grendel (NL) determined that the area of the monomolecular film formed on a Langmuir trough by the membrane lipids was double the surface area of the erythrocytes from which the lipids had been extracted, suggesting that the cell membrane is bimolecular (1059). This was the first evidence that cell membranes are bi-layered.

William Rowan (CH-CA) used dark-eyed juncos, Junco hyemalis, to demonstrate that changes in ambient photoperiod can profoundly affect the activity of the bird’s reproductive system. He proved that the annual cycle of changing day-length is the major stimulus for bird migration and is associated with profound physiological change within birds (2308-2310).

Robert Kyle Burns, Jr. (US) established the adequacy of the hormonal theory of sex determination as a general mechanism for vertebrates (359-364). See Frank Rattray Lillie, 1916.

Ernest Henry Starling (GB) and Ernest Basil Verney (GB) isolated dog kidneys, which they supplied with oxygenated blood at controlled flow rates, temperature, and pressure. They found they could produce regular flow rates of normal urine. From their analysis of the urine they determined that the glomeruli generate a protein-free filtrate. They artificially blocked tubular metabolic activity with hydrocyanic acid, collected ureter filtrate, and found that water, chloride, bicarbonate, and glucose are normally reabsorbed from the glomerular filtrate by the tubular cells. They also found that pituitrin (a proprietary preparation of the posterior lobe of the pituitary gland) influenced the re-absorption mechanisms for water and chloride and that without it the mammalian kidney reverted to a urine characteristic of fish and amphibian classes (2613). Vasopressin would later be isolated as the active ingredient in pituitrin.

Edwin B. Hart (US), Harry Steenbock (US), Conrad Arnold Elvehjem (US), and James Waddell (US) demonstrated that when rabbits were induced into a state of anemia by milk diet, the addition of ferric salts alone was insufficient to bring about recovery. They discovered that the additional presence of copper is necessary for the animals to synthesize the pyrrol nucleus of hemoglobin (1170, 1171).

Louis Sigurd Fridericia (DK) and Eiler Holm (DK) demonstrated that vitamin A (retinol) is necessary for normal night vision in rats. They also found that both the retinas of A-deficient rats and of rats whose eyes had been strongly illuminated were depleted of visual purple (952).

Simeon Burt Wolbach (US), Otto A. Bessey (US), and Percy R. Howe (US) concluded that vitamin A (retinol) deficiency in diets led to improper development of teeth and retardation of the growth of the skeleton and that vitamin C deficiency led to a deficiency of formation of intercellular cement substance leading to fragility of blood capillaries (3043-3048).

J.H.C. Ruyter (BE) was the first to call attention to the structural peculiarities of unique cells lining the afferent arteriole as it approaches the glomerulus. He suggested that by swelling these cells could occlude the lumen of the afferent arterioles and thereby regulate blood flow to the glomerular capillaries (2331).

Norbert Goormaghtigh (BE) named the juxtaglomerular apparatus and suggested that it might have an endocrine function (1045).

Norbert Goormaghtigh (BE) and Keith S. Grimson (US) confirmed that the modified cells in the afferent arteriolar wall of the juxtaglomerular apparatus are endocrine in nature (1046-1053).

They also observed that occasionally crosses produced female-biased sex ratios, a clear violation of Mendel’s first law. Daughters from the distorted brood produced an equal number of males and females, but half of their sons produced female-biased sex ratios, whatever the origin of their mates. The remaining grandsons produced normal sex ratios and were shown to have lost the trait (1917).

David Policansky (US) and John Ellison (US) showed that in the Drosophila males producing biased sex ratio offspring there is a high mortality among sperm bearing the Y chromosome. They concluded that in some way a gene on the X chromosome kills sperm bearing a Y chromosome (2116).

Felix Bernstein (DE) proposed that the human ABO blood group is inherited in a multiple allele pattern (198).

Hermann Joseph Muller, Jr. (US) reported on the mental traits and heredity as studied in a case of identical twins reared apart (1935).

Horatio H. Newman (US), Frank N. Freeman (US), and Karl J. Holzinger (US) presented a large study of heredity and environment in the development of 100 pairs of twins (1980).

Carl Hamilton Browning (GB) defined substances that incite the formation of antibodies and react with them as antigens (322).

John Cunningham (GB), working in India, found that the organism, Borrelia carteri, occurs in two antigenic varieties in human infections of relapsing fever (577). John Cunningham (GB), J.H. Theodore (GB), and A.G.L. Fraser (GB) extended the number of antigenic varieties to nine (578).

William George Savage (GB) and Philip Bruce White (GB) laid the groundwork for antigenic analysis of the Salmonella group (2368).

Gaston Ramon (FR) demonstrated that it was possible to augment the antitoxin response to diphtheria and tetanus by administering vaccines with pyogenic bacteria or with various additional compounds. This represents the first occasion on which immunological adjuvants were used. Ramon called them adjuvantes et stimulantes de l’immunite (2159).

Porter Warren Anderson, Jr. (US) and David Hamilton Smith (US), Richard B. Johnston, Jr. (US), Michael E. Pichichero (US), Richard A. Insel (US), Robert Frank Betts (US), and Ronald J. Eby (US) made the first polysaccharide-conjugate vaccines against Haemophilus influenzae to be tested in adults and infants (56, 57). They went on to develop a vaccine, which was a commercial success.

Louis P. Rodriques (US), John B. Robbins (US) Rachel Schneerson (US), James C. Parke, Jr. (US), C. Bell (US), James J. Schlesselman (US), Ann Sutton (US), Z. Wang (US), Gerald Schiffman (US), Arthur Karpas (US), and Joseph Shiloach (US) studied the antigenicity of the Haemophilus influenzae type b (Hib) polysaccharide then developed a clinically acceptable method of binding this polysaccharide to a medically useful protein, tetanus toxoid to form a conjugate vaccine. In sequential studies, their Hib-tetanus conjugate elicited protective levels in mice, rabbits, young rhesus monkeys, and then in human adults, children, and infants. Their achievement opened the door to their and others' development of conjugate vaccines for other bacterial pathogens whose surface polysaccharide could serve as a protective antigen (2271, 2395, 2396).

William C. Boeck (US) and Jaroslav Drbohlav (US) were the first to develop in vitro cultures of Endamoeba histolytica. They grew it in a diphasic egg slant medium they developed for isolation of intestinal flagellates (241).

Alfred Stock (DE) wrote about the danger of mercury vapor and concluded that mercury is a poison, which can accumulate in the tissues over a considerable period of time (2641).

Martha Schmidtmann (DE) by following the spread of dye in cardiac cells presented the first evidence for a direct intercellular pathway permeable to molecules (2393).

Walther Vogt (DE) prepared a fate map that showed where the cells on the surface of an early gastrula would be in the later embryo. That is, he determined the destiny, or fate, of the gastrula cells (2818, 2819).

Nicole Le Douarin (FR), Claude Le Lièvre (FR), and Marie-Aimée Teillet (FR) used chick-quail chimeras to track the fate of neural crest cells and found that many of them migrate to form a variety of structures (1604-1606).

John Thomas Scopes (US) was the defendant in Tennessee v. John Thomas Scopes, the so-called monkey trial held in Dayton, Tennessee in July 1925, in which a science teacher was arrested for teaching evolution in violation of the state laws at that time. Two-time presidential candidate William Jennings Bryan led the prosecution. Labor lawyer Clarence Darrow led the defense and goaded Bryan into declaring that humans are not mammals (2741).

George Hoyt Whipple (US), Frieda Saur Robscheit-Robbins (US), C. Arthur Elden (US), Warren M. Sperry (US), and George B. Walden (US) found that liver, heart, skeletal muscle, ash of liver, ash of kidney, and ash of pineapple promotes regeneration of hemoglobin following severe anemia (2266-2269, 2963, 2964). These results suggested that iron in the diet is important for hemoglobin formation.

George Hoyt Whipple (US) and William Leslie Bradford (US) coined the word thalassaemia deriving it from two Greek words - Thalassa meaning the sea and haima meaning blood, literally "sea water in the blood" (2962).

Arnold Rice Rich (US) concluded that hemoglobin, derived from destroyed erythrocytes, is the sole source of bile pigment; its normal site of origin being in reticuloendothelial cells alone, especially the Kupffer cells, and the epithelial liver cells having no role in the formation, but only in the excretion of the bile pigment (2223).

Percival Bailey (US) and Harvey Williams Cushing (US) postulated that medulloblastomas (Bailey coined this name) are derived from embryonic undifferentiated cells in the ependymal lining of the fourth ventricle. They described the characteristic gross and microscopic structure of this tumor, its reddish-gray color, extremely cellular nature, numerous mitotic figures, and the formation of pseudo rosettes. The tendency of this tumor to spread to the leptomeninges, which proved valuable in terms of treatment considerations, was noted. They recommended radiotherapy in the post-operative care of patients with medulloblastomas (100, 103).

Erich Urbach (AT-US) presented a diagnostic procedure for demonstrating antibodies in allergics. Allergen administered by either the percutaneous, cutaneous, or intracutaneous routes causes a local reaction, which will develop into a blister when a cantharidal dressing is placed on it (2762).

Walter Edward Dandy (US) reported a case in which he totally removed an acoustic neuroma (AN). He used a unilateral sub occipital approach during which, following gutting of the tumor, he gently drew the capsule away from the brainstem (604). Dandy's success was due in part to his innovation called ventriculography, which involved x-rays and injecting a gas into the brain's cerebral ventricles for visualizing the tumor. See, Dandy 1918.

Percy Sargent (GB) was the first to remove a suprarenal tumor thus reversing virilism in the patient. Gordon Morgan Holmes (GB) described the operation (1260).

Geoffrey Jefferson (GB) performed the first successful embolectomy in Britain (1359).

Konstantine Michaelovich Bykov (RU) was the first to demonstrate experimentally that the bilateral synergic activity of the hemispheres of the brain may be dependent on the corpus callosum, and indicated the part the corpus callosum plays in the development of symmetrical reproduction of function in the hemispheres. He severed the corpus callosum in dogs and then used Ivan Pavlov's classical conditioning methods to assess the effects of his surgeries. His experiments showed the importance of the corpus callosum for interhemispheric communication (381, 382).

Howard J. Curtis (US) and Archibald Philip Bard (US) used electrical stimulation to prove the point-to-point connection of one side of the cortex to the other by way of the corpus callosum (579).

Howard Christian Naffziger (US) described the phenomenon of the pineal shift on skull x-rays, an important sign for brain tumor localization (1956).

Egas Moniz (PT) developed cerebral angiography, the technique of using x-rays to visualize arteries and veins thus permitting the diagnosis of several kinds of neurological disorders, such as tumors and arteriovenous malformations (1906).

John Silas Lundy (US), in 1925, developed the concept of balanced anesthesia. He introduced the idea of combining more than one anesthetic technique—for example, using morphine preoperatively, a regional block to the surgical site, alongside an inhalational anesthetic of ethylene (1723).

Hermann Ludwig Blumgart (US) and Otto Christian Yens (US), in 1925, performed the most famous of all radiotracer experiments on humans, the well-known study of arm-to-arm circulation time (237). This ushered in the field of nuclear medicine.

Wolfgang Köhler (DE) showed that instead of learning simply by trial and error chimpanzees are able to solve problems by grasping the relations between means and ends, i.e., they displayed insight (1480).

Merritt Lyndon Fernald (US) proved that in the northeastern United States some species of plants and animals persisted in areas that escaped glaciation during the Pleistocene (889).

Fritz Berckhemer (DE) found a fossil skull of a young female in the Sigrist gravel pit north of Stuttgart, Germany and gave it to Karl Sigrist (183, 184). This, so called, Steinheim skull can be considered a Homo erectus/Homo sapiens transitional form from the Middle Pleistocene, ca. 4000,000 B.P.

Raymond Arthur Dart (AU-ZA) found in material from a limestone quarry at Taung (place of the lion), South Africa a fossil cast of the inside of a primate skull, which fitted into another lump of stone which possibly contained a face. It took Dart about a month to remove enough stone to reveal the face and jaw of a young fossil primate, which would be nicknamed the Taung baby. Dart considered the fossil “an extinct race of apes intermediate between living anthropoids and man.” He described it and named it Australopithecus africanus (Southern ape from Africa) and dated it to between 3 and 2.3 Ma (613). It was placed in early Pleistocene or late Pliocene.

Australopithecus africanus existed between 3 and 2 million years ago. It is similar to A.afarensis, and was also bipedal, but body size was slightly greater. Brain size may also have been slightly larger, ranging between 420 and 500 cc. This is a little larger than chimp brains (despite a similar body size), but still not advanced in the areas necessary for speech. The back teeth were a little bigger than in A.afarensis. Although the teeth and jaws of A.africanus are much larger than those of humans, they are far more similar to human teeth than to those of apes. The shape of the jaw is now fully parabolic, like that of humans, and the size of the canine teeth is further reduced compared to A.afarensis (489, 1362).

The American Type Culture Collection was founded. It is a repository and source of known strains of viruses, bacteria, fungi, algae, and eukaryotic cells.

1926

“Men fear thought as they fear nothing else on earth—more than death. Thought is subversive, and revolutionary, destructive and terrible; thought is merciless to privilege, established institutions, and comfortable habits; thought is anarchic and lawless, indifferent to authority, careless to the well-tried wisdom of the ages. Thought looks into the pit of hell and is not afraid.…Thought is great and swift and free, the light of the world, and the chief glory of man.” Bertrand Russell (2329).

“The striking similarity established by Meyerhof between the changes of carbohydrates in muscle and in the yeast cell is seen to be much closer than has been believed. The remarkable phenomena accompanying alcoholic fermentation are now duplicated in the case of lactic acid production, and it may reasonably be expected that most of the fermentative decompositions of sugars will be found to be initiated in a similar manner.” Arthur Harden (1155).

“The characters of the individual are referable to paired elements (genes) in the germinal matter that are held together in a definite number of linkage groups…. The members of each pair of genes separate when germ cells mature…. Each germ-cell comes to contain only one set…. These principles…enable us to handle problems of genetics in a strictly numerical basis, and allow us to predict…what will occur…. In these respects the theory [of the gene] fulfills the requirements of a scientific theory in the fullest sense.… It is difficult to resist the fascinating assumption that the gene is constant because it represents an organic chemical entity. This is the simplest assumption that one can make at present, and since this view is consistent with all that is known about the stability of the gene it seems, at least, a good working hypothesis.” Thomas Hunt Morgan (1915).

Theodor Svedberg (SE) was awarded the Nobel Prize in Chemistry for his work on disperse systems.

Johannes Andreas Grib Fibiger (DK) was awarded the Nobel Prize in Physiology or Medicine for research indicating that a nematode, Spiroptera carcinoma, caused gastric cancer in rats (895). The hypothesis was later rejected but, nonetheless, had an important role in the development of experimental research on cancer.

Gilbert Newton Lewis (US) coined the term photon for the smallest unit of radiant energy (1650).

The Commission on Units and Measurements defined the röntgen at the Second International Congress of Radiology in Stockholm, Sweden. It was based on ionization of air.

Leopold Stefan Ruzicka (HR-CH) analyzed civetone and muscone, two active compounds in natural musk perfumes and found that they consist of very large rings of atoms. He showed that civetone is composed of a 17 membered, and muscone a 15 membered carbon ring. At this time it was thought that rings with over 6 members were too unstable to exist for long (2332). This paper was submitted in 1924.

Hans Karl August Simon von Euler-Chelpin (DE-SE), Christian Barthel (LU), and Karl Myrbäck (SE) found that dried yeast possess practically the same power of fermentation as fresh yeast although they retain only 1% of the reproductive power (129, 2829).

Julio Caesar Tello (PE) was inspired by the discovery in 1910 of the Paracas Textile (ca. 100 B.C.E.) at the site of Cabeza Larga on the Paracas Peninsula on the South coast of Peru. In his 1925 excavations Tello found coca leaves placed in an urn, which accompanied the burial of a Peruvian priest, noble, or king from the Nazca period. This is the earliest record of the use of cocoa leaves (2698).

Albert Jan Kluyver (NL) and Hendrick Jean Louis Donker (NL) wrote their treatise on the unity of biochemistry in which they stressed that biochemical mechanisms can be investigated using mutant strains of microorganisms and that hydrogen transfer is a basic feature of all metabolic processes (1466).

Juda Hirsch Quastel (GB-CA) and Barnet Woolf (GB) published the first reported measurementof the equilibrium constant of an enzyme-catalyzed reaction. It was on the aspartateammonia-lyase reaction (2148).

James Batcheller Sumner (US) was the first to obtain an enzyme in pure crystalline form. This was the enzyme urease, which catalyzes the hydrolysis of urea to yield carbon dioxide and ammonia. Sumner had used a 32% solution of acetone in water to precipitate much of the organic material in a jack-bean extract rich in urease activity, while leaving most of the urease activity in solution. After filtering off this precipitate and letting the filtrate stand overnight in the cold, he found that crystals of protein had formed in the filtrate. Study of these protein crystals revealed that they are pure urease enzyme endowed with a specific enzymatic activity enormously greater than that of the original jack-bean extract. It was thus proven that the enzyme urease is a protein and that a polypeptide chain is capable of acting as a catalyst in the facilitation of a chemical reaction.

Sumner’s proof was an important milestone along the road to understanding the chemical basis of cell function (2665).

Calvin Blackman Bridges (US) and T.M. Olbrycht () noted that in order to accurately construct genetic maps it is necessary to know the full number of crossovers (doubles counting as two, triples as three crossovers) that occur between the loci that are to be mapped. In constructing such maps it is first necessary to determine experimentally the amounts by which the various crossing over values exceed the directly observed recombination percents. The experimental determination of the amount by which crossing over exceeds recombination is made through use of loci lying between the twoloci in question. Bridges created the sc ec ct v g fmultiple recessive and called it "Xple" (X-chromosome multiple). This organism was used to test many aspects of linkage mapping (296).

Edgar Altenburg (US) and Hermann J. Muller (US) demonstrated the nature of the mechanism of inheritance of the truncate character in Drosophila. They showed that it conformed regularly to the principles of chromosome heredity, factor constancy, etc., and disclosed the causes of the inconstancy of the inbred stock, and of the indefiniteness and variability of the ratios thrown in crosses. The truncate character, when it was analyzed, was found to depend on so many factors. 1) Two successive mutations were practically necessary, in the first place, before truncate became visible at all. 2)Since truncate depended on a lethal, and was, in addition, inconstant in somatic expression, it was subjected to selection, which perpetuated any new factors (balancing lethals and intensifiers) that still further differentiated truncate from normal. 3) Since the truncate character depended on an unstable developmental reaction, the initial appearance of such intensifiers was made more likely (48).

Edgar Douglas Adrian (GB) and Yngve Zotterman (SE), using the afferent nerve of a stretch receptor in a frog muscle, showed that it is possible by amplification to record the impulses in single nerve cells to a natural stimulus (tension). They postulated the concept of adaptation of receptors to stimuli and predicted that other units of the nervous system would also exhibit adaptation (16).

Edgar Douglas Adrian (GB) and Yngve Zotterman (SE), established beyond doubt that the nerve impulse is invariant, that the intensity of sensation is conveyed by the frequency of impulses and the quality by the type of nerve fiber in action (16).

Eugene Markley Landis (US), Schack August Steenberg Krogh (DK), and Abbey H. Turner (US), in an elegant series of experiments, determined that the rate of net fluid movement across the capillary wall is proportional to the difference between capillary hydrostatic pressure and the osmotic pressure of the plasma proteins, thus providing the first experimental proof of Ernest Starling’s hypothesis of fluid exchange. Landis’s constant of proportionality was the first quantitative measurement of the hydrodynamic conductance of the capillary wall (cubic microns of fluid per second per centimeter water pressure difference per square micrometer of capillary wall). These papers included the first measurements of the pressure drops along the vascular tree and localization of the separate components of the peripheral resistance to blood flow, in mammals as well as frogs (1529, 1565-1577). See, Starling 1896.

John Belling (GB-US) perfected the aceto-carmine staining method by adding iron. This technique was especially important because it allowed a clear differentiation between chromosomes and cytoplasm (173).

Gaston Ramon (FR) and Pierre A. Descombey (FR) described the flocculation reaction and observed that flocculation may occur in zones that do not correspond to the point at which the toxin and antitoxin neutralize each other (2161).

Kenjiró Fujii (JP) observed the coiled structure of the chromosome for the first time noting that in certain stages of the cell cycle, two filaments were seen to be coiled around each other (969).

Frantisek Vejdovsky (CZ) showed that nuclear fission in an ovule is preceded by the splitting of the centrosome (which he called the periplast); he was apparently the first to observe the centriole in 1866 (2796).

Félix Hubert d’Herelle (CA) described the three-step process for the life history of the bacteriophage virus: (1) attachment to the susceptible bacterium, (2) multiplication in the cell, and (3) disintegration of the cell to set free the progeny virus particles and attachment of the progeny to other susceptible bacteria, if such are present. These conclusions were based on the plaque-count, and dilution methods of assay that he had invented (586).

Thomas Clifford Vanterpool (CA) was the first to discover that mixed infections, the simultaneous occurrence of two viruses within a host plant acting together, could produce a distinct severe disease. He showed that tomato mosaic virus and potato mosaic virus acting together caused the severe disease of tomatoes called streak or winter blight while either virus acting alone was shown to cause mild symptoms (2794).

Andre Paillot (FR) discovered granulosis virus (GV) infection in an insect, Pieris brassicae (cabbage butterfly). He was the first to describe a new group of diseases, the granuloses, which are characterized by the formation of virus inclusion bodies called granules within tissues of infected insects (2025). }. These are now considered Baculovirus.

Edson Sunderland Bastin (US) succeeded in culturing sulfate-reducing bacteria from groundwater samples extracted from an oil deposit that was hundreds of meters below the surface. Since this discovery over 9,000 strains of bacteria and fungi have been isolated from diverse subsurface environments (135, 946).

Heinrich Bernward Prell (DE) reported an amoebic infection of an insect, Apis mellifera Linn. (honeybee). The etiological agent he described and named Malpighamoeba mellificae attacks the Malpighian tubules causing a dysentery (2132, 2133).

Everitt George Dunne Murray (CA), Robert Alexander Webb (GB), and Meredith Blake Robson Swann (GB) isolated and characterized Listeria monocytogenes as the etiological agent of an epizootic among laboratory rabbits and guinea pigs, which was characterized in part by monocytosis (1950).

Louis Edmond den Dooren de Jong (NL) demonstrated that a strain of Pseudomonas putida can proliferate on a mineral medium to which any one of some eighty compounds was added as the sole organic substance available (627).

Maurice Lemoigne (FR) originally discovered poly-beta-hydroxybutyric acid (PHB) as a major component of the cells of the bacterium Bacillus megaterium (1626).

Frank W. Tilley (US) and Jacob M. Schaffer (US) determined that the germicidal activity of the aliphatic alcohols increases regularly from methyl through octyl alcohol for each additional methyl group in the straight chain (2379, 2725).

John Nathaniel Couch (US) described for the first time the existence of physiologically distinct and separate male and female strains in an oomycete (Dictyuchus) (556).

Friedrich Seidel (DE), using eggs of the dragonfly, Platycnemispennipes, determined that embryonic development in insects is typified by the presence of a special kind of germ-band formation. Because of the distribution of cytoplasm and yolk in the egg the germ band is limited to a particular region. The ventral portion of the developing embryo is special because it is the carrier of the main system of organs. The ventral part of the embryo precedes the dorsal side in development (2431-2433).

Alden B. Dawson (US) carried out the first successful skeletal staining when he used alizarin red S (619).

Henry Allan Gleason (US) argued that every plant association is the unique product of the fluctuating environmental conditions of a particular time and place (1034).

Gavin Rylands de Beer (GB) observed that certain cartilage and bone cells are derived from the outer ectodermal layer of the embryo; calling into question the germ-layer theory (622).

Sergei S. Chetverikov (RU) concluded that populations in nature maintain within themselves the variants, which arise within them by mutation. This would provide them with a supply of potential but hidden variability out of which the adaptiveness of the population to a changing environment could arise (450, 451).

William Bloom (US) worked out the early stages of the embryogenesis of human bile capillaries (229).

William Bloom (US) described the transformation of small lymphocytes into myelocytes in germinal centers (230).

George Ellett Coghill (US), in his studies of the amphibian Amblystoma punctatum, established that innervation develops in a cephalo-caudal (head-tail) direction, and that limb movements emerge from a more general pattern of trunk movement. He then theorized that behavior develops as the expansion of a "total pattern," rather than simply as the combination or coordination of reflexes, and suggested strongly that this might well be true for higher vertebrates, including man (490-493).

Serge Metalnikov (RU-FR) and V. Chorine (FR) provided an important paper in psychoneuroimmunology when they adapted Pavlov’s procedures of stimulant conditioning to activate and enhance cellular and antibody immune responses to foreign substances, particularly to otherwise lethal doses of cholera and anthrax bacteria (1853).

Erik Adolf Willebrand (FI) described a previously unknown form of hemophilia with a prolonged bleeding time course as its most prominent sign. He named it pseudo-hemophilia (2998-3000). Willebrand’s disease I.

Nikolai Mikhailovich Itsenko (RU) described glucocorticoid excess syndrome in which the hypersecretion of glucocorticoids is secondary to hypersecretion of adrenocorticotrophic hormone from the pituitary. It may also be caused by a basophilic adenoma of the pituitary (1346).

Harvey Williams Cushing (US) described this syndrome six years later (582). It is often called Cushing’s syndrome I but should be called Itsenko-Cushing syndrome.

Felix Mandl (AT) was the first to undertake parathyroid surgery, successfully removing a parathyroid adenoma in a patient with osteitis fibrosa cystica (1758).

Henry Head (GB) presented his theory of aphasia as a condition with ”a disorder of symbolic formulation and expression” (1192).

César Roux (CH) performed the first surgical resection of a pheochromocytoma, in 1926 (1760). Later the same year, Charles Horace Mayo (US) performed the first surgical resection in the United States and described medical and surgical management of pheochromocytoma (1804).

Percival Bailey (US) and Harvey Williams Cushing (US) wrote a book, which formed the basis of modern day neurooncology. It completely revolutionized the understanding of neurooncology, and for first time the neurosurgical community was presented with an orderly classification of gliomas based on the tumor's natural history and clinical course. This work changed antiquated thinking by showing that the microscopic structure of a tumor is important for prognosis. It completely revamped the understanding of these tumors. In fact, the histopathological basis of brain tumors in relation to patient survival rate and outcome still influences present-day neurosurgical thought (104).

Percival Bailey (US) simplified, refined, and made the concepts presented in the 1926 book more practical (98, 99).

Harvey Williams Cushing (US) and William T. Bovie (US) conceived and introduced electrosurgery, which allowed the cutting of tissue with almost no bleeding. During 1927, Cushing removed a number of brain tumors previously considered inoperable (584, 2244).

Maximilian Carl-Friedrich Nitze (DE), in 1896, developed an operating cystoscope fitted with an electric cautery (1988).

Francis Bertody Sumner (US) made a thorough study of coat color among the mainland and Santa Rosa Island mice, and concluded that both isolation and natural selection probably operated in the origin of species, but that environmental mechanisms could not be ruled out. Though still not conclusive, Sumner’s reading of nature’s experiments on Santa Rosa came closer than any other study at the time — field or lab — to providing empirical evidence of the mechanism of evolution. Santa Rosa is an island off the Florida panhandle (2663).

1927

Heinrich Otto Wieland (DE) was awarded the Nobel Prize in Chemistry for his investigations of the constitution of the bile acids and related substances.

Julius Wagner-Jauregg (AT) was awarded the Nobel Prize in Physiology or Medicine for his discovery of fever therapy for paresis (dementia paralytica). He shared the honor with the pathologist Johannes Andreas Grib Fibiger (DK), who was awarded the prize "for his discovery of the Spiroptery carcinoma."

Alexander Logie du Toit (ZA) compared the geology of South America and South Africa and found them to be similar in many ways (737).

Hans Busch (DE) theorized that magnetic fields could act as lenses by focusing electron beams to a point (369). This was vital to the invention of the electron microscope.

Hermann Joseph Muller, Jr. (US) and Lewis John Stadler (US) discovered that x-rays induce mutations in animals and plants respectively. They found that the dose-frequency curve is linear (1936, 2597, 2598).

Albert Charles Chibnall (GB) and Harold John Channon (GB) discovered the exact structure of phosphatidic acid; described for the first time in living materials (453).

Rudolph John Anderson (SE-US) isolated the various lipoid and carbohydrate fractions from the tubercle bacillus. He was able to separate the lipoid constituents of tubercle bacilli into three groups consisting of wax, glycerides, and phosphatides (58).

Rudolph John Anderson (SE-US) described the constitution of phthiocol, a fat-soluble pigment he isolated from human tubercle bacillus. He determined that this previously unknown substance was in fact 2-methyl-3-hydroxy-1, 4-naphthaquinone (60).

Otto Fritz Meyerhof (DE-US) discovered that the first step in the fermentation of glucose (glucose to glucose-6-phosphate), catalyzed by an enzyme he called hexokinase, does not require inorganic phosphate but rather organic phosphate transferred from its terminal, or g position on adenosine triphosphate (ATP) (1859).

Hans Karl August Simon von Euler-Chelpin (DE-SE) showed for the first time a combination between an enzyme and a substrate that was traced back to a certain atomic group (carbonyl group). He was experimenting with dipeptidases (2827).

Otto Paul Hermann Diels (DE), Willy Gädke (DE), and Anna Karstens (DE) used selenium to dehydrogenate cholesterol thus yielding Diels’ hydrocarbon, an aromatic hydrocarbon closely related to the skeletal structure of all steroids, of which cholesterol is one (689, 690).

Otto Paul Hermann Diels (DE) and Hermann Klare (DE), in 1934, put forth the correct structure of Diels’ hydrocarbon as 3'-methyl-1, 2-cyclopentaphenanthrene. This work represents a dramatic turning point in the understanding of the chemistry of cholesterol and other steroids.

Juda Hirsch Quastel (GB-CA) and Walter Reginald Wooldridge (GB) studied dehydrogenases from Escherichia coli and further developed the concept of the active center, or site of activation, a term earlier coined by Quastel (1926). This work stressed the importance of using in vitro results to understand in vivo activities of enzymes (2146). They also discovered that malonic acid is a powerful inhibitor of succinic dehydrogenase (2147).

Philip Eggleton (GB) and Marion Grace Palmer Eggleton (GB) found an organic acid-labile phosphate in muscle tissue. They named it phosphagen (creatine phosphate) and established the fact that muscular contraction is accompanied by removal of phosphagen, and subsequent recovery in oxygen is characterized by a rapid restitution of the phosphagen—a phase of recovery apparently independent of the relatively slow oxidative removal of lactic acid (795).

Cyrus Hartwell Fiske (US) and Yellapragada SubbaRow (US) discovered the chemical nature of the phosphagen (creatine phosphate)present in muscles. They announced that voluntary muscle contains an unstable compound of creatine and phosphoric acid, which is hydrolyzed by stimulation, and resynthesized when the muscle is permitted to recover. They proposed a structure and pointed out some of the physiological properties of phosphocreatine (later changed to creatine phosphate) (910, 911, 913). Note: Michel-Eugène Chevreul (FR), in 1832, determined that muscle contains creatine (452).

Bernhard Zondek (DE-IL) and Selmar Aschheim (DE) isolated estrogenic hormone from the urine of pregnant women in amounts averaging 12,000 mouse units per liter (3110). They found that the urine of pregnant women, when injected into female animals, causes hyperemia of the ovaries, growth of the follicles, and, in some species ovulation (76). This became the basis of the Ascheim-Zondek and Friedman-Lapham Tests for pregnancy.

Maurice H. Friedman (US) and Maxwell Lapham (US) developed the "Rabbit test" for early diagnosis of pregnancy. Two morning samples of urine were injected into the marginal ear vein of a virginal female rabbit that had been isolated from male rabbits. The result was available 48 hours after the first injection. Of all the biologic tests, Friedman's was the most accurate. This procedure tested for the presence of human chorionic gonadotropin (hCG; a hormone released from the implantation site of a blastocyst that prevents menstruation) in the urine of women. If hCG were present in the urine, the rabbit's ovaries would form corpora lutea (ovarian endocrine structures formed following ovulation) within 48 hours (955, 956).

Julius Moses Rogoff (US) and George Neil Stewart (US) demonstrated that a chemical extract of the adrenal glands of dogs greatly prolongs the lifespan of adrenalectomized dogs. They found that the active ingredient was not epinephrine (adrenaline) (2273). They experienced some success in using adrenal extract to treat human patients suffering from Addison’s disease (2274). Charles-Édouard Brown-Séquard (FR) had proved that removal of both suprarenal (adrenal) glands invariably proved fatal. See, Brown-Séquard, 1856.

Joseph Barcroft (GB) and J.G. Stephens (GB) demonstrated the spleen's role as a blood reservoir in the dog (120).

Thomas Milton Rivers (US) clearly distinguished between bacteria and viruses, thereby, giving rise to the field of virology (2251).

Nicolaas Louis Söhngen (NL) was probably the first to report bacteria that lyse other bacteria, in some cases with a high degree of parasite-host specificity. Bacterium bacteriovorus, which lyses Bacillus danicus, he found to grow only in the presence of its host (2551).

Ronald Aylmer Fisher (GB-AU) explained the evolution of Batesian mimicry by a series of small evolutionary steps. He proposed that the phenotypic expression of genes could be modified by the action of other genes. Rare imperfect mimetic forms when they appeared in a population would vary due to the action of modifier genes. Selection would favor those modifier genes that produced an increase in the accuracy of the mimicry (904).

John Charles Walker (US) pioneered research on genetic resistance in yellows disease of cabbage. He showed the scientific community that disease control through genetic resistance could be an effective and relatively inexpensive approach to solving plant disease problems (2880, 2881).

Emil Bozler (DE-US) demonstrated that the nerve net of cnidarians is made up of separate cells connected by synaptic junctions. He also studied electrical aspects of muscle contraction and the role of calcium and magnesium in contraction and relaxation (270).

James R. Archer (GB), Steven J. Self (GB), and Bryan G. Winchester (GB) explained the t-complex in mice as a genetic entity which alters meiosis is such a way that its transmission into gametes is favored (69). The t-complex is located on the proximal third of chromosome 17 in the house mouse. Naturally occurring variant forms of the t-complex, known as complete t-haplotypes, are found in wild mouse populations. The t-haplotypes contain at least four nonoverlapping inversions that suppress recombination with the wild-type chromosome, and lock into strong linkage disequilibrium.

Barbara C. Turner (US) and David D. Perkins (US), working with Neurospora, discovered spore killer, a chromosomal factor that kills meiotic products in which it is not contained (2755).

Laurence Sandler (US) and Kent G. Golic (US) discovered segregation distorter (Sd), a meiotic drive system that operates in males of Drosophila melanogaster. Males heterozygous for Sd, a dominant neomorphic (gain-of-function) mutation on chromosome 2, can transmit their progeny in greater frequencies than expected on a Mendelian basis (2355).

Arthur M. Massee (GB) was the first to demonstrate this to be the case (1797).

Erwin Stresemann (DE) wrote an important volume on bird biology as part of Kükenthal and Krumback’s Handbuch der Zoologie. It contains thorough discussions of avian physiology, anatomy, and other phases of avian biology (2655).

Theophilus Shickel Painter (US) studied the Japanese Waltzer mouse and concluded that its phenotype results from a chromosomal deletion (2026) This was the first cytological identification of a deletion producing a specific genetic effect and the first case in mammals of locating a definite gene on a definite chromosome.

Thomas Lewis (GB) originally described the wheal and flare reaction. He described how he believed histamine to be crucially involved in the central area of the weal, where it then stimulates an axon reflex or antidromic reflex, which transmits the signal to more distant parts, i.e., the flare (1654).

Matthew Walzer (US) and Sampson J. Wilson (US) demonstrated that the ingestion of foods would allow food antigens to penetrate the gastrointestinal barrier, which are then transported in the circulation to IgE-bearing mast cells in the skin (2892, 3029). The IgE class of immunoglobulin was not discovered until 1967.

David Marine (US) and Emil J. Baumann (US) found that administration of Ringer’s solution and isotonic solutions of sodium chloride and sodium acetate increased the life span of suprarenalectomized cats about three fold (1768).

Soma Weiss (HU-US) developed the first practical method of measuring circulation in time (2937).

Wallace Osgood Fenn (US) was the first to measure the quantity of oxygen required by a nerve to conduct an impulse (869).

Otto Heinrich Warburg (DE), Harry Goldblatt (US), Gladys Cameron (US), Fritz Kubowitz (DE), Karlfried Gawehn (DE), August-Wilhelm Geissler (DE), Detlev Kayser (DE) and Siegfried Lorenz (DE) provided the very unexpected and fundamental fact, that tissue culture is carcinogenic and that a too low oxygen pressure is the intrinsic cause. Anaerobiosis of cancer cells was an established fact by 1960 when methods were developed to measure the oxygen pressure inside of tumors in the living body (1037, 2896, 2909-2911).

Mark W. Woods (US), Katherine K. Sandford (US), Dean Burk (US), and Wilton R. Earle (US) found that cancer cells, descended in vitro from one single normal cell, were in vivo the more malignant, the higher their fermentation rate (3067).

Dean Burk (US), Mark W. Woods (US), and Jehu Hunter (US) found that when different carcinogens were used to induce in vivo hepatomas there was a direct correlation between malignancy and fermentation rate (343).

Thomas Benton Cooley (US), E.R. Witwer (US), and O. Pearl Lee (US) described the disease, which later became known as Cooley erythroblastic anemia (533).

Guido Fanconi (CH) reported a family in which three brothers had died in childhood from a condition, which resembled pernicious anemia. He observed that these children had slight stature, hypogonadism and skin pigmentation. In subsequent reports defects of the thumb and radius were recognized as additional but variable syndromic components (859). This became known as Fanconi’s anemia.

Philip Edward Smith (US) perfected the surgical production of hypophysectomized rats and described the symptoms resulting as inhibition of growth in the young animal, weight loss, atrophy of the genital system with loss of libido sexualis, cessation of the female sex cycle, atrophy of the thyroid, parathyroids and suprarenal (adrenal) cortex, lowered resistance to injury, loss of appetite, weakness, and flabbiness. Smith found that he could reverse the atrophied functions in these animals only by injection of fresh hypophyseal tissue from adults. These animals have been widely used in studies of the endocrine system (2539).

Ugo Cerletti (IT) and Lucio Bini (IT) introduced electric convulsive therapy (E.C.T.) for severe mental states. This treatment was first used in schizophrenia, but severe depressive states very soon proved to be the main indication (423, 424). Note: people used electric eels and electric fish in ancient times to treat headaches and mental illness.

Jean Delay (FR) and Pierre Deniker (FR) demonstrated success with the first neuroleptic—coined by Delay— drug, the phenothiazine derivative chlorpromazine (Thorazine). Chlorpromazine has a remarkable effect on patients with schizophrenia, in particular highly agitated, anxious, and psychotic patients. It softens the effects of hallucinations and voices. Patients became quiet and much more manageable. It has effects on all types of patients (643).

Fritz Eichholtz (DE) and Otto Butzengeiger (DE) carried out the first experimental use of avertin (2,2,2-tribromoethanol) as an anesthetic in animals (799).

Major Greenwood (GB) and Janet Elizabeth Lane-Claypon (GB) developed a key type of epidemiological investigation, the so-called "case-control study". They tracked down 500 women with a history of breast cancer- the “cases” - and compared them with 500 women who were free of the disease but otherwise broadly similar, known as “controls”. The detailed survey that emerged constituted, as far as is know, the first published epidemiological questionnaire. This yielded results that enabled them to identify many of the risk factors for breast cancer that are still considered valid today. Their conclusions (or their data reworked by later researchers) agreed with those of modern reviewers: breast cancer was associated with age at menopause, artificial menopause, age at first pregnancy (age at marriage used as a proxy), number of children, and lactation.

They published what is now considered the first “end results” study. It followed a large sample of women with pathologically confirmed breast cancer for up to 10 years after their surgery. The study confirmed that women who were surgically treated at an early stage of the disease had a much better chance of surviving three, five, or 10 years longer than those operated on at any later stage. They showed that breast cancer risk increased for childless women, women who married later than average, and women who did not breast feed. The overall breast cancer risk decreased according to the number of children. For all cases, rapid treatment held the key to survival among women with breast cancer. In reviewing the family histories of their cases, they anticipated the role that genes might play in the development of breast cancer. “There appear to be some families,” they wrote, “in which for reasons not certain at present, cancer plays havoc with the members, and there is (some) slight evidence in some instances that it attacks the same organs” (1082).

Charles Sutherland Elton (GB) redefined the species niche by emphasizing its functional role in the community: the niche is “the status of an animal in its community.” His concept idealized what the species does rather than where it lives—the functional niche concept (818).

Erik Anderson Stensiö (SE) reconstructed a fossil Cephalaspis (an ostracoderm) and suggested its status as a vertebrate prototype replacing amphioxus (2626). Note: it is generally believed that living Agnatha (hagfishes and lampreys) and the ostracoderms are descended from a common ancestor.

Arturo Palma di Cesnola (IT) and Borzatti von Löwenstern (IT), in 1964, found two deciduous molars in the so-called Uluzzian archaeological layers unearthed from the Grotta del Cavallo (Southern Italy). Classified as Neanderthal and dated to 45,000 years ago these fossils are the oldest known human remains on the continent (680).

Stefano Benazzi (AT), Katerina Douka (GB), Cinzia Fornai (AT), Catherine C. Bauer (DE), Ottmar Kullmer (DE), Jiří Svoboda (CZ), Ildikó Pap (HU), Francesco Mallegni (IT), Priscilla Bayle (FR), Michael Coquerelle (ES), Silvana Condemi (FR), Annamaria Ronchitelli (IT), Katerina Harvati (DE) and Gerhard W. Weber (AT) reanalyzed the deciduous molars from the Grotta del Cavallo (Southern Italy), associated with the Uluzzian and originally classified as Neanderthal. Their new chronometric data for the Uluzzian layers of Grotta del Cavallo obtained from associated shell beads and included within a Bayesian age model show that the teeth must date to ~45,000–43,000 calendar years before present. The Cavallo human remains are therefore the oldest known European anatomically modern humans, confirming a rapid dispersal of modern humans across the continent before the Aurignacian and the disappearance of Neanderthals (177).

1928

"Only when some important function... lends itself to ready observation or quantitative measurement are the conditions suitable for making progress..." Edwin B. Hart, et al., (1171).

“As I view my contribution to the writing of our time, it seems to me to consist of a double affirmative, saying first that an awareness and experience of Nature is necessary to Man if he is to have his humanity, and saying in the second place that that same awareness must have something of a religious quality, the Italian pieta, if you will.

Nature is a part of our humanity, and without some awareness and experience of that divine mystery man ceases to be man. When the Pleiades and the wind in the grass are no longer a part of the human spirit, a part of the very flesh and bone, man becomes, as it were, a kind of cosmic outlaw, having neither the completeness and the integrity of the animal nor the birthright of a true humanity.” Henry Beston (203).

Adolf Otto Rheinhold Windaus (DE) was awarded the Nobel Prize in Chemistry for research into the constitution of the sterols and their connection with the vitamins.

Charles Jules Henri Nicolle (FR) was awarded the Nobel Prize in Physiology or Medicine for his work on typhus.

Otto Fritz Meyerhof (DE-US) and Karl Lohmann (DE) isolated argininephosphoric acid from arthropod (crustacean) muscle. It was found to be the invertebrate analogue of the vertebrate phosphagen (creatine phosphate) (1860, 1875, 1876).

Karl Lohmann (DE) and Hermann Lehmann (DE) demonstrated that phosphagen (creatine phosphate) reacts with ADP in minced crustacean muscle (1619, 1696). This provided, for the first time, a mechanism for utilization of phosphate energy. This became known as the Lohmann reaction.

Marjory Stephenson (GB) obtained the first cell-free preparation of non-NAD dependent lactic dehydrogenase, which oxidized lactate to pyruvate in the presence of methylene blue (2628).

James Waddell (US), Conrad Arnold Elvehjem (US), Harry Steenbock (US), Edwin Bret Hart (US), Evelyn Van Donk (US), and Blanche M. Riising (US) discovered that inorganic iron salts are ineffective at increasing the hemoglobin levels of anemic rats, but that ashed residues from dried beef liver, dried lettuce, and yellow corn were very effective in curing anemia. From these results they inferred that the extracts contained some other inorganic substance that was necessary for the production of hemoglobin. They later discovered that this necessary substance was copper (2847).

James Waddell (US), Harry Steenbock (US), Conrad Arnold Elvehjem (US), Edwin Bret Hart (US), and Evelyn Van Donk (US) found that copper-containing liver extracts and a copper sulfate solution both served equally well in curing anemia in rats. This led them to the conclusion that, “the deficiency (in this anemia) is inorganic in nature and that this inorganic deficiency is copper only” (2848).

Hubert Bradford Vickery (CA-US) and Charles S. Leavenworth (US) carried out an analysis of the basic amino acids in horse hemoglobin and concluded that the protein contains 7.64% histidine, 3.32% arginine, and 8.10% lysine. These results were in agreement with the assumption that hemoglobin has 33 molecules of histidine, 13 molecules of arginine, and 37 molecules of lysine (2806).

Bertil Hanstöm (SE) discovered that the X-organ, located in the eyestalk of crustaceans, secretes neurohormones (1152-1154). Neurosecretory cells in the X-organ (part of the brain) produce a molt-inhibiting hormone that is stored in the sinus gland of the eyestalk, while a molting hormone is produced in the Y-organ. Interactions of these two hormones control the molting process.

Bernhard Zondek (DE-IL) and Selmar Aschheim (DE) isolated from the anterior pituitary gland a gonadotropic hormone they named prolan (it was luteinizing hormone-LH-and/or follicle stimulating hormone-FSH) (3111). Prolan is a term no longer in use.

Fritz Albert Lipmann (DE-US), Vladimir Aleksandrovich Engelhardt (RU), and A.P. Barkash (RU) presented evidence for the metabolic pathway from glucose-6-phosphate to triose phosphate by way of ribose-5-phosphate. They called it the hexose monophosphate shunt (841, 1685).

Frederick Griffith (GB) discovered the transforming factor while working with Diplococcus pneumoniae (Streptococcus pneumoniae). He demonstrated that this factor, which he isolated from smooth colonies, is a chemical that is present in the extract of dead smooth colonies, but missing from live rough colonies. When mixed with living rough colonies the transforming factor converted many of them to living smooth colonies (1084).

James Lionel Alloway (US), working in the laboratory of Oswald Theodore Avery (CA-US), broke open cells of the smooth form of pneumococcus and collected the cell contents, which were passed through a filter that would remove all wall material. When this extract was added to a culture of growing rough cells some of them were transformed into smooth cells. When the transforming extract was treated with alcohol a thick syrupy precipitate formed (40).

Oswald Theodore Avery (CA-US) would later show that the transforming factor is DNA. See, Sanfelice, 1893 and Avery, 1944.

Albert Imre Szent-Györgyi (HU-US) using the adrenal cortex, cabbage, and orange as raw material isolated and crystallized a factor which he knew was in some way involved in the mechanism of biological oxidation. He named this acidic carbohydrate hexuronic acid (2674).

Charles Glen King (US) and William A. Waugh (US) succeeded in obtaining Szent-Györgyi’s hexuronic acid in crystalline form then equated it with vitamin C (1448, 2924). Today it is known as ascorbic acid (ascorbic meaning, no scurvy) or vitamin C.

Cornelis Bernardus Kees van Niel (NL-US), working with propionic acid bacteria, provided the first quantitative picture of the products derived by these bacteria from lactate, glycerol, glucose, and starch. His taxonomic treatment determined the veracity of the genus Propionibacterium. During these studies he identified diacetyl as the compound responsible for the characteristic aroma of high quality butter (2782).

Herbert McLean Evans (US) and Miriam E. Simpson (US) found that extracts from the anterior pituitary cause hypertrophy of the mammary glands in virgin rats (852).

Oscar Riddle (US) and Pela Fay Braucher (US) showed that extracts of the anterior lobe of the pituitary gland could cause the enlargement and functioning of the crop-glands in pigeons (2243).

Oscar Riddle (US), Robert Wesley Bates (US), and Simon William Dykshorn (US) reported their discovery of a hormone produced in the anterior pituitary gland, which stimulates the crop-gland in pigeons and is lactogenic in guinea pigs; they named it prolactin (2241, 2242).

Eva Nagy (HU-CA) and Istvan Berczi (HU-CA) reported that regulation of the immune response by the neuroendocrine hormone prolactin (PRL) occurs via its interaction with the prolactin receptor. Interference with this ligand-receptor interaction inhibits both in vitro and in vivo immune responses (1962).

Charles V. Clevenger (US), Amy L. Sillman (US), Michael B. Prystowsky (US), Yi-Ping Rao (US), Donna J. Buckley (US), Mark D. Olson (US) and Arthur R. Buckley (US) showed that prolactin is able to physically enter the cell, travel straight to the cell’s DNA, and directly activate the process that turns on genes and triggers the growth of breast cancer cells. It does this by binding to a protein called cyclophilin B, or CYPB for short (485, 2165).

Georg von Békésy (HU-US) elucidated all the physical events at every strategically important point in the transmission system of the ear by recording events in this fragile biological miniature system, micro dissection, advanced teletechniques for stimulation and recording, and high magnification stroboscopic microscopy. He elucidated the vibration patterns of the eardrum and the interplay of the ossicle movements, provided experimental and clinical data confirming Helmholtz’s assumption that the frequency of the sound waves determines the location along the basilar membrane at which stimulation occurs. He found that movements of the stirrup footplate evokes a wave complex in the basilar membrane, which travels from the stiffer basal part to the more flexible part in the apex of the cochlea. The crest of the largest wave first increases, thereafter quickly decreases. The position of the maximal amplitude was found to be dependent on the frequency of the stimulating sound waves in such a way that the highest crest of the travelling wave appears near the apex of the cochlea at low-frequency tones and near its base at high frequencies (2821-2824, 2839).

Donald Dexter van Slyke (US) and Julius Sendroy, Jr. (US) reported studies of gas and electrolyte equilibria in blood in which they present line charts for graphic calculations by the Henderson-Hasselbalch equation, and for calculating plasma carbon dioxide content from whole blood content (2791). Van Slyke continued to improve this method through eleven more papers.

Thomas Hunt Morgan (US) presented the theory of the gene when he said, “The theory states that the characters of the individual are referable to paired elements (genes) in the germinal material that are held together in a definite number of linkage groups; it states that the members of each pair of genes separate when the germ-cells mature in accordance with Johann Gregor Mendel’s first law, and in consequence each germ-cell comes to contain one set only; it states that the members belonging to different linkage groups assort independently in accordance with Johann Gregor Mendel’s second law; it states that an orderly interchange—crossing over— also takes place, at times, between elements in corresponding linkage groups; and it states that the frequency of crossing over furnishes evidence of the linear order of the elements in each linkage group and of the relative position of the elements with respect to each other” (1916).

Hermann Joseph Muller, Jr. (US) and Theophilus Shickel Painter (US) using Drosophila, carried out parallel investigations in which phenotypic variations brought about by x-rays were related to physical changes in the chromosomes, e.g., deletions and translocations (1937, 2028).

Eggert Hugo Heiberg Møller (US), John F. McIntosh (US), and Donald Dexter van Slyke (US) determined that a constant volume of blood is being cleared of urea in each minute’s time course. This came to be referred to as standard blood urea clearances (1904).

Renjiro Kaneko (JP) and Yoshio Aoki (JP) determined that the etiological agent of Japanese B encephalitis was probably a virus (1402).

M. Hayashi (JP) transmitted Japanese encephalitis— one of the leading causes of acute encephalopathy— from an infected human to monkeys by way of an intracerebral injection to prove the viral etiology of the disease (1190).

Arthur T. Henrici (US) reported that the average size of bacterial cells might vary considerably from one growth phase to another during a growth cycle (1212).

Clifford Dobell (US) was the first to describe encystment of a parasitic amoebic form, Entamoeba histolytica (697).

Kenneth L. Burdon (US) described Bacteroides melaninogenicus in the stools of patients suffering from chronic amebic dysentery, and in puerperal sepsis. This bacterium is often associated with the mouth, tonsils, infected abdominal wounds, and focal infections of the kidneys (341).

Henry E. Meleney (US) presented clear evidence of the development of six immunologically distinct strains of Borrelia recurrentis (1847).

Karl Johannes (Hans) Kniep (DE) and Arthur Henry Reginald Buller (CA) had previously presented the broad picture of the genetic control system and the developmental sequence from spore to spore in the basidiomycetes (337, 1469). Buller was also a poet. One of his most recognized works is this limerick, first published in the Dec. 19, 1923 issue of Punch:

Herbert Friedmann (US) described social parasitism among birds and wrote, The Cowbirds: A Study in the Biology of Social Parasitism, a definitive treatment of brood parasitism (957, 958). This type of behavior is seen among the cuckoos, cowbirds, honey guides, and weaverbirds.

Archibald Philip Bard (US) discovered that the emotion we call rage depends on neurons in the caudal half of the hypothalamus (121-124).

John F. Fulton (US) reported on a patient presenting with an arteriovenous malformation of the occipital cortex. Surgical removal of the malformation was attempted but was unsuccessful, leaving the patient with a bony defect over the primary visual cortex. Fulton elicited a history of a cranial sound audible to the patient whenever he engaged in a visual task. Based on this history Fulton pursued a detailed investigation of the behavior of the sound that he could auscultate and record over the occipital cortex. Remarkably consistent changes in the character of the sound could be appreciated depending upon the visual activities of the patient. Although opening the eyes produced only modest increases in the intensity of the sound, reading produced striking increases (977). Cortical blood flow is thus related to the complexity of the visual task and the attention of the subject to that task.

Hans Zinsser (US) and H. Yu (US) were among the first to suggest that diseases such as rheumatic fever and glomerulonephritis result from hypersensitivity to toxins produced by certain strains of streptococci (3103, 3105).

George Nicholas Papanicolaou (Greek-US) and Herbert Frederick Traut (US) developed the Cervical Smear (Pap smear for Papanicolaou) Test for the detection of uterine cancer. It is based on the cytological examination of cells exfoliated from the uterus (2031-2033).

Selmar Aschheim (DE) and Bernhard Zondek (DE-IL) reported their pregnancy test (Aschheim-Zondek Pregnancy Test) for humans, “Our test is carried out with morning urine…. The urine is injected subcutaneously into the infantile [female mice]…. Only the ovarian findings are of significance for the pregnancy reaction [enlargement with follicular maturation]…. We have examined 78 cases of pregnancy. In 76 cases the reaction was definitely positive…. In [the] 198 control cases the reaction was positive twice…. The reaction thus has a precision that one cannot hope to surpass with a biologic method” (74, 75).

Owen Harding Wangensteen (US) and George W. Waldron (US) did studies in intestinal obstruction, which led to the development of the Wangensteen suction technique to relieve increased internal viscus pressure in the stomach and intestine resulting from excess gastric and intestinal secretions in an atonic intestine (2893).

Percival Bailey (US) and Harvey Williams Cushing (US) were the first to describe the condition known as fugitive acromegaly, in which patients may exhibit physical stigmata of acromegaly without biochemical evidence of the disease (105).

Andrew Ellicott Douglass (US) discovered that annual growth of tree rings could be used to construct a window on the weather of the past. Trees add a layer of wood to their trunks every year - a wide ring during wet years and a thin one during dry years. By matching ring patterns in living trees to the patterns in old timbers, the record could be extended further back into history, i.e., dendrochronology (728). This method is most accurate from the present to 12,000 years ago.

Adolf Remane (DE), working in the Kiel Bight (Baltic Sea) in 1928, discovered the new phylum Gnathostomulida (jaw worms), a small (0.5 mm long) marine worm-like form with worldwide distribution (2219).

Peter Ax (DE) originallydescribed Gnathostomulida as an order of the Platyhelminthes (91, 92).

John Burdon Sanderson Haldane (GB-IN), in 1928, wrote the essay, On Being the Right Size, which Jane Jacobs and others have since referred to as Haldane's principle. This is that sheer size very often defines what bodily equipment an animal must have: “Insects, being so small, do not have oxygen-carrying bloodstreams. What little oxygen their cells require can be absorbed by simple diffusion of air through their bodies. But being larger means an animal must take on complicated oxygen pumping and distributing systems to reach all the cells” (1132).

1929

“Everything is determined… by forces over which we have no control. It is determined for the insect as well as for the star. Human beings, vegetables, or cosmic dust—we all dance to a mysterious tune, intoned in the distance by an invisible piper.” Albert Einstein (466, 801).

Arthur Harden (GB) and Hans Karl August Simon von Euler-Chelpin (DE-SE) were awarded the Nobel Prize in Chemistry for their investigations on the fermentation of sugar and fermentative enzymes.

Christiaan Eijkman (NL) for his discovery of the antineuritic vitamin (thiamine, vitamin B1) and Frederick Gowland Hopkins (GB) for his discovery of the growth-stimulating vitamins shared the Nobel Prize in physiology and medicine.

Dame Kathleen Yardley Lonsdale (GB) was the first to use x-ray diffraction to solve the structure of an organic molecule, she showed that hexamethylbenzene is planar and hexagonal - and gave its precise dimensions (1707).

Sergei Yakovievich Sokolov (RU) suggested the concept of the pulse-echo ultrasonic metal flaw detector (2552). This instrument was the precursor of subsequent pulse-echo medical ultrasonic (ultrasound) devices operating in the uni-directional A-mode and used as early as 1949 by Lars Leksell (SE) and J.C. Turner (GB) for examining brain lesions (1622, 1623).

Walter Norman Haworth (GB) determined that a number of stereo isomeric structures are possible for the pyranose ring of each sugar and showed that glucose in the six-member (pyranose) form is more stable than when it is in the five-member (furanose) form or in the Fischer form, i.e., Haworth structures for sugars (1183).

Karl Lohmann (DE) determined its structure and recognized it to be adenosine-5’-triphosphate (ATP). Lohmann (DE) also characterized adenosine-5’-diphosphate (ADP) (1697).

John Howard Northrop (US) isolated swine pepsin in pure crystalline form by techniques, which were later used by him and other workers to crystallize trypsin, chymotrypsin, carboxypeptidase, and pepsinogen (1994).

Marjorie Martland (GB) and Robert Robison (GB) observed that during the hydrolysis of fructosediphosphate (fructose-1,6-diphosphate) by preparations of bone phosphatase, a part of the sugars liberated, following the removal of the phosphoric acid groups, suffered an intramolecular change and gave rise to a mixture of aldolase and ketose sugars (1790).

Phoebus Aaron Theodor Levene (RU-US) and Efim Semenovich London (RU) isolated and described 2-deoxyribose (they called it thyminose because it came from thymus nucleic acid, i.e., DNA, as belonging to a group of pentoses lacking an oxygen atom, and hence named desoxypentoses then later named deoxypentoses (1638, 1639).

George Oswald Burr (US), Mildred M. Burr (US), and Elmer S. Miller (US) demonstrated the existence and necessity of the so-called essential fatty acids. At that time, essentiality meant promotion of growth and prevention of the dermatitis observed when a fat-free diet was fed to rats (365-367).

Michel Macheboeuf (FR) isolated the first plasma lipoprotein to exhibit a constant composition (1743). This fraction was later characterized as an alpha-1-globulin that we now recognize as high-density lipoprotein (HDL).

Karl Paul Gerhard Link (US), Herbert Raleigh Angell (GB-AU), Allan D. Dickson (US), and John Charles Walker (US) established for the first time a specific chemical difference between a resistant host (pigmented onion) and a non-resistant host (the white onion). They determined that the brown-pigmented onion produces the antifungal agent protocatechuic acid, which the white onion lacks (1682-1684).

George Washington Corner (US) and Willard Myron Allen (US) found,.…” that alcoholic extracts of the corpus luteum, freed of phospholipids, contains a substance which when injected into castrated adult female rabbits induces a characteristic alteration of the endometrium identical with the progestational proliferation previously shown to be due to the presence of corpora lutea in the ovaries.” They called this substance progestin (progesterone) (553).

Barnet Woolf (GB) was the first to site an example of an enzyme forming a complex with two substrates; later called ternary complexes (3070). He proposed a theory of enzymatic action in which the binding of substrate or substrates leads to chemical transformation of the substrate at the specific binding site of the enzyme (3071).

Carl Ferdinand Cori (CZ -US) and Gerty Theresa Cori, née Radnitz (CZ -US) concluded from work begun in 1925 that, “Formation of liver glycogen from lactic acid is thus seen to establish an important connection between the metabolism of muscle and that of the liver. Muscle glycogen becomes available as blood sugar through the intervention of the liver, and blood sugar in turn is converted into muscle glycogen. There exists therefore a complete cycle of the glucose molecule in the body, which is illustrated by the diagram: blood glucose — muscle glycogen — blood lactic acid — liver glycogen — blood glucose.

Epinephrine (adrenaline) was found to accelerate this cycle in the direction of muscle glycogen to liver glycogen and to inhibit it in the direction of blood glucose to muscle glycogen; the result is an accumulation of sugar in the blood. Insulin, on the other hand, was found to accelerate the cycle in the direction of blood glucose to muscle glycogen, which leads to hypoglycemia and secondarily to a depletion of the glycogen stores of the liver … There is also a possibility that other hormones besides epinephrine [adrenaline] and insulin influence this cycle” (543).

Carl Peter Henrik Dam (DK) discovered vitamin K while working with chickens on synthetic diets. It seemed to be necessary for normal blood clotting so he named it vitamin K, for koagulation (the German spelling). Dam, Fritz Schönheyder (DK), and Erik Tage-Hansen (DK) discovered that the blood of chickens became depleted of prothrombin when they were placed on a vitamin K deficient diet (596-599, 601, 602).

Ernst Franz Moro (AT-DE) introduced the use of raw apples as well as a carrot soup in the treatment of diarrheic conditions in infants (1921). This was based on an old custom among German peasants.

Tobias L. Birnberg (US) reported the successful treatment of diarrhea, dysentery, colitis, and celiac disease in children by restricting their diet to raw apple (210).

Michael Heidelberger (US) and Forrest E. Kendall (US) established the principle of quantitative immunochemistry when they perfected the quantitative precipitin reaction (1198).

William Hay Taliaferro (US) wrote The Immunology of Parasitic Infections, a pioneering book in this branch of immunology (2685).

Theodosius Grigorievich Dobzhansky (UA-US), Theophilus Shickel Painter (US), and Hermann Joseph Muller, Jr. (US) showed that while the linear sequence of genes is the same for genetic and cytological maps, physical distances and crossover map distances did not coincide (701, 702, 1940, 2027).

Frank Macfarlane Burnet (AU) and Margot McKie (AU) attributed the permanency of the lysogenic character in bacteria to the presence of an entity they called anlage which is capable of liberating bacteriophage. Anlage was conceived as a normal hereditary constituent of lysogenic bacteria and, unless activated, no liberation of bacteriophage resulted (355).

C. Eugene Woodruff (US) and Ernest William Goodpasture (US) supplied the first direct evidence of the relation of viral inclusion bodies and elementary bodies to virus (1044, 3062).

Francis O. Holmes (US) arrived at the first practical and accurate method for the quantification of plant virus infectivity by counting the local lesions developing in the leaves of tobacco (Nicotiana species) (1259).

Howard Bancroft Andervont (US) showed that the herpes virus of man could be transmitted to mice by intracerebral inoculation, and thereby provided the means of studying this human virus in an animal (63).

Aage Nyfeldt (DK) reported that Listeria monocytogenes is capable of causing an infection in man (listeriosis) although it had been known to be infectious for domestic and feral animals since 1911. The organism derives its name from the striking monocytic blood reaction it causes in the infected host (2001).

Clifford Dobell (GB) and Ann Bishop (GB) described the life cycle of Entamoeba histolytica (698).

Warren Harmon Lewis (US) and Margaret Reed Lewis (US) were the first to develop time-lapse microscopic motion pictures to record observations on living cells in culture. Their films became important teaching resources in cytology, and led them to develop mechanical theories of cell motion. In one of their first films they were able to see the early development of rabbit embryos, from the first ovum cleavage to the blastocyst stage.

Homer William Smith (US) became the first researcher to report that the gills are the major sites of nitrogen excretion in freshwater fish. His experimental subjects were the common carp (Cyprinus carpio) and goldfish (Carassius auratus) (2528).

Derek Ernest Denny-Brown (NZ-GB-US) introduced electromyography (EMG) as a clinical tool and initiated the procedure of muscle biopsy as a means of seeking a direct tissue diagnosis of neuromuscular diseases (658).

George Bernays Wislocki (US) and James Peter Hill (GB) determined that all the primates, except the lemurs, have discoidal or doubly discoidal placentas of hemochorial type. In Old World forms, the shape of the placenta in the Ceropithecidae (macaques, langurs, etc.) is usually doubly discoidal; the baboons, in which it is singly discoidal, are the exception. In the Hylobatidae, Pongidae, and Hominidae (anthropoid apes and man) it is always singly discoidal. A completely villous discoidal placenta is seen only in the gorilla, orangutan, and man (1229, 3040). At this point in history the placenta of the chimpanzee had not received a thorough microscopic study.

Heinrich Pette (DE) proposed that inflammatory diseases of the nervous system be divided into two groups: (1) acute inflammatory diseases predominantly of the gray matter, and (2) acute inflammatory diseases predominantly of the white matter (2087).

Maxwell Myer Wintrobe (CA-US) invented what became known as the Wintrobe hematocrit (3033).

Donald Macomber (US) and Morris B. Sanders (US) reported their results of analyzing the spermatozoa count to determine its value in the diagnosis, prognosis and treatment of sterility. They reported the normal sperm density to be 100 million sperm/mL. Their number was based on the sperm counts of 294 individuals without regard to fertility status. In addition, they reported that men with sperm densities less than 60 million/mL rarely were capable of initiating a pregnancy (1752).

Edgar Otto Conrad von Gierke (DE) described a common member of a group of hereditary glycogen-storage diseases. This progressive disease is an inborn error of glycogen metabolism due to glucose-6-phosphatase (G6P) deficiency, involving chiefly the liver and kidneys (2838). The liver may become huge and contain as much as 15 percent of glycogen. It is sometimes called Gierke's disease.

Otto Hermann Krayer (DE-US) mastered the heart-lung-preparation (HLP) originally developed by Starling in England. He used the HLP to show that an oxidation product of Neosalvarsan is toxic to vascular beds in a number of organs (1506, 1507). This is one of the reasons that this anti-syphilitic arsenical drug ceased to be used.

Otto Hermann Krayer (DE-US) perfected the management of the heart-lung-preparation (HLP) to the point that he could make quantitative measurements of the activity of cardioactive drugs. He also developed a standard HLP procedure to study drug effects on the failing heart (1508-1514).

Wilhelm Sigmund Feldberg (DE-GB) and Otto Hermann Krayer (DE-US) used both intact dogs and cats, as well as, dog and cat HLPs to show that an “acetylcholine-like substance” is released into the coronary circulation of mammals upon electrical stimulus of the vagus nerve (866).

Albert Wollenberger (DE) and Otto Hermann Krayer (DE-US) demonstrated a method for quantitatively determining the limits of cardiac sufficiency in response to specific measured changes in right arterial pressure. They developed a specific “competence index” to express the heart’s response numerically. This method allows a clear distinction to be made between drugs that primarily affect heart rate and those (like digitalis) that truly improve the work capacity of the impaired muscle (3050).

Philip Drinker (US) and Charles F. McKhann (US) invented a new apparatus (the iron lung) for the administration of artificial respiration over prolonged periods of time (733).

Walter Edward Dandy (US) introduced the practice of removing an intervertebral disk to alleviate lower back pain, sciatica, and other symptoms caused by a ruptured disk (606).

Harold Brunn (US) reported six lobectomies (removals of lung lobes) for bronchiectasis with only one death. In bronchiectasis one or more bronchi or bronchioles are chronically dilated and inflamed, with copious discharge of mucus mixed with pus. The secret of Brunn's success was the use of intermittent suction after surgery to keep the cavity free of secretions until the remaining lobes of the lung could expand to fill the space (327).

Frederic Edward Clements (US), John Ernst Weaver (US), and Herbert C. Hanson (US) stated that one of the important processes directing plant succession is competition between similar plants leading ultimately to a climax community (481).

Percival Bailey (US) and Paul Clancy Bucy (US) were the first to confirm the existence of tumors that were, in fact, composed of oligodendroglia and to establish this type of glioma as a definite entity (102).

Karl S. Lashley (US) promulgated the theory of cortical specialization for sensory and motor functions. He challenged the ongoing concept of cortical localization. Lashley brought the controversy between localization and holistic emphasis of brain function into focus. He is remembered as a great psychologist who approached learning and memory by assessing the effects of brain damage in laboratory animals (1598, 1599).

Wolfgang Köhler (DE) and Kurt Koffka (DE) promoted a pattern theory of memory. Diffuse neural groupings mediated memory. They hypothesized that multiple memory traces were formed in the cortex. Visual memories involved successive and simultaneous stimuli in different parts of the visual field. They postulated that new records might be inscribed on top of old patterns these could affect one another leading to a newly organized group-unit (1476, 1481).

Johanna Gabrielle Ottilie Edinger (DE-US) demonstrated that the evolution of the brain could be studied directly from fossil cranial casts (782). She later showed that the progression of brain structure does not proceed at a constant rate in a given family but varies over time; also that the enlarged forebrain evolved several times independently among advanced groups of mammals and there was no single evolutionary scale (783).

1930

“The most beautiful thing we can experience is the mysterious. It is the source of all art and science,” Albert Einstein (802, 1794).

“The scientific attitude of mind involves a sweeping away of all other desires in the interest of the desire to know—it involves suppression of hopes and fears, loves and hates, and the whole subjective emotional life, until we become subdued to the material, without bias, without any wish except to see it as it is, and without any belief that what it is must be determined by some relation, positive or negative, to what we should like it to be or to what we can easily imagine it to be.” Bertrand Russell (2330).

“No myth of miraculous creation is so marvelous as the fact of man’s evolution.” Robert Briffault (298).

Hans Fischer (DE) was awarded the Nobel Prize in Chemistry for research into the constitution of hemin and chlorophyll and especially for the synthesis of hemin.

Karl Landsteiner (AT-US) was awarded the Nobel Prize in Physiology or Medicine for his discovery of human blood groups.

A.A. Lebedeff (RU) designed and built the first interference microscope (1611).

Sterling Brown Hendricks (US) and William H. Fry (US) presented what is arguably the most important elucidation of the nature and properties of soils. They conclusively proved the crystalline nature of colloidal clay with the prevalence of negative charges that will absorb and release cations. These findings led to an understanding of the chemistry necessary to maintain high potential in soil productivity, and in providing a valid chemical basis for the reclamation of the alkali soils of arid regions (1209).

William Thomas Astbury (GB), Henry J. Woods (GB), and A. Street (GB), using x-ray diffraction, demonstrated for the first time a measurable change in protein structure at the most intimate molecular level—interatomic shifts of a few ångströms. This change was found to be reversible. They called the two forms alpha-keratin and beta-keratin (81-83).

Hermann Bortels (DE) reported that nitrogen fixation by Azotobacter has a requirement for molybdenum (258).

Rudolph J. Anderson (US) reported myoinositol as a lipid constituent in the phospholipids of mycobacteria (59).

Wilbur Willis Swingle (US), Joseph J. Pfiffner (US), Frank A. Hartman (US), and Katherine A. Brownell (US) were the first to prepare extracts from the adrenal cortex, which successfully controlled the symptoms of adrenal insufficiency both in adrenalectomized animals and in patients who had Addison’s disease (1176, 2670, 2671).

William Smith Tillett (US) and Thomas Francis, Jr. (US) discovered that the C-fraction carbohydrate from pneumococci stimulates the production of a non-antibody globulin, which they dubbed C-reactive protein (CRP) (2719).

Subsequently it was found that C-reactive protein appears in the blood of patients in response to many infections. During recovery from infection the C-reactive protein (CRP) diminishes in amount and within a few days disappears entirely. The serum of an animal immunized to CRP is used in a Precipitation Test to detect CRP in sera of persons suspected of having one of the diseases in which the protein appears, e.g. staphylococcal infection.

Ejnar Lundsgaard (DK) discovered that frog muscle poisoned with iodoacetic acid—which inhibits glycolysis—could contract without the formation of lactic acid, but with the disappearance of creatine phosphate. Once the creatine phosphate was exhausted the muscles went into a rigor mortis like condition. He wrote, “… phosphagen (creatine phosphate) is the substance directly supplying the energy for contraction, while lactic acid formation in the normal muscle continually provides the energy for its resynthesis” (1722). Lundsgaard had discovered that the muscle machine could be driven by phosphate-bond energy.

Ragnar S. Nilsson (SE) isolated phosphoglyceric acid from natural sources. Based on the action of dried yeast on a mixture of glucose, hexosephosphate, and acetylaldehyde he suggested that glyceraldehyde-phosphate might play a role in the glycolytic breakdown of carbohydrate (1986).

Fritz Breinl (CZ) and Felix Haurowitz (CZ-US) published their template theory of antibody formation (288). Although incorrect, this theory and others stimulated research.

H. Lyndhurst Duke (GB) and James Montague Wallace (GB) gave the first description of a complement receptor activity on erythrocytes (749).

James Montague Wallace (GB) and Arthur Wormall (GB) proposed that complement is required for this adherence reaction (2888).

Haldan Keffer Hartline (US) and Clarence H. Graham (US) used tiny electrodes to determine how single retinal nerve cells in horseshoe crabs and frogs receive information and transfer it to the brain (1173).

Haldan Keffer Hartline (US) mapped the activity of the visual receptive field to reveal a system of many convergent pathways from many photoreceptors (1172). This work laid the foundation for modern concepts of parallel processing by specialized channels.

Yandell Henderson (US), Howard W. Haggard (US), Pol N. Coryllos (GR-US) and George L. Birnbaum (US) found that in dogs with experimentally induced pneumonia the lungs may be cleared and the pneumonia cured by placing the animals in an atmosphere of about 8% carbon dioxide for 12 to 24 hours. In support of the claim that these are real cures is the fact that pneumococci are inhibited in growth or even killed by a lowering of pH no greater than carbon dioxide may induce. A lowering of the pH by carbon dioxide contributes also to the autolysis and liquefaction of the exudate responsible for the consolidation of the lungs in pneumonia. Many cases of pneumonia have now been treated by inhalation of a carbon dioxide-oxygen mixture in a special tent introduced by Henderson and Haggard. This treatment is decidedly superior to treatment with oxygen alone (1207).

Benjamin Freeman Kingsbury (US) in his studies of neuroembryonic development provided the first detailed discussion of the possible functions of the floor plate in neural development (1451).

Ronald Aylmer Fisher (GB-AU) wrote The Genetical Theory of Natural Selection. This book contained his fundamental theorum of natural selection: “The rate of increase in fitness of any organism at any time is equal to its genetic variance in fitness at that time.” Natural selection is viewed as always tending to increase fitness, in the sense of reproductive fitness, and the course of evolution being determined by the momentary advantage of one allele over the other. This work formalized the relation of particulate genes to the evolutionary process. It overturned the old theory of heredity as blending, on which Charles Robert Darwin (GB) had based his views of the operation of natural selection (905).

Lewis John Stadler (US) devised and perfected methods for determining rate of spontaneous mutation in maize, finding that different genes mutate at widely different rates (2599-2601).

Norman H. Giles, Jr. (US) found that in Neurospora crassa quantitative mutability of different loci varies in spontaneous mutation (1028).

Herbert Friedmann (US) studied the honey-guides—family Indicaroridae—of Southern Rhodesia (Zimbabwe) and South Africa. He confirmed, first hand, that these birds do indeed lead a symbiont, often man, who opens the hive and removes some of the honey, the bird, then feeds on the wax comb (959-963).

Herbert Friedmann (US) and Jerome Kern (US) determined that honey-guides possess a digestive enzyme and a microbial symbiont both of which attack the beeswax, thus making it available for further digestion (964, 965). Wax eating is called cerophagy.

Charles Benedict Davenport (US) published a short pedigree, which demonstrates linkage between hemophilia and red-green color-blindness in man (615).

Charles Cyril Okell (GB) and Adelaide V. Blake (GB) determined that the Shiga exotoxin is released following autolysis or disruption of the bacterial cells; suggesting that it is an endotoxin (2008).

Bert Cyril James Gabriel Knight (GB) and Paul Gordon Fildes (GB) initiated studies, which led to the understanding that some heterotrophic bacteria can grow on a simple medium containing inorganic ions, ammonium as nitrogen source and glucose as source of carbon and energy. Other species are unable to grow on such a medium unless it is supplemented by an amino acid or one of the B group of vitamins. Still others, particularly those found in chemically complex habitats, require several amino acids and several vitamins before they could grow. Fildes and his colleagues postulated that the nutritional requirements are a reflection of the synthetic disabilities of the organisms concerned: that an organism that requires a specific amino acid for growth has, in the course of its evolution, lost the ability to synthesize that amino acid which is nevertheless an essential part of its cellular material. This postulate meant that nutritional studies could be used to study stages in biosynthesis (1471).

Max Theiler (ZA-US) and Hugh H. Smith (US) grew the yellow fever virus in rhesus monkeys (Macacus rhesus), and then passed it to mice. In mice, it developed as encephalitis. They passed it from mouse to mouse, and then eventually back to monkeys. By this time it had attenuated, producing a very mild attack in the monkeys, but producing a full immunity to the most virulent form of the virus. This attenuated strain could also be used to vaccinate man (2706, 2707).

Samuel Phillips Bedson (GB), George T. Western (GB), Samuel Levy Simpson (GB), and John O.W. Bland (GB) were outstanding early students of the Bedsonia —later called Chlamydiae. They discovered that Chlamydia psittaci/Chlamydophila psittaci is the etiological agent of parrot fever (psittacosis) (158, 159).

Homer William Smith (US) determined that in order for marine teleosts to maintain their blood salinity below that of the surrounding waters they rely upon a relatively impermeable skin, drink sea water to replace water lost through the gill membranes, and secret salt using a special transport mechanism located in the gills. Elasmobranch fishes solve this problem by making their tissues isosmotic or slightly hyperosmotic to seawater using a build-up of urea. He found that the elasmobranch kidney conserves urea by tubular reabsorption (2529, 2531, 2532).

Malcolm S. Gordon (US), Knut Schmidt-Nielsen (DK-US), and Hamilton M. Kelly (US) found that the crab-eating frog (Rana cancrivora) is the only known amphibian, which can tolerate seawater. It does so by raising its blood osmolarity using urea (1055).

Homer William Smith (US) found that in order to prevent desiccation, lungfishes burrow deep into the mud and form a cocoon with a breathing channel to the surface. They may remain dormant for up to two years during which time course their body proteins are gradually utilized and their tissue urea levels may reach 3 percent (2530).

Charles Haskell Danforth (US) established the basic conditions for understanding the mechanisms for production of sex plumage in birds. He found in Ring-necked pheasants the sex characteristics of the plumage are dependent upon simultaneous action of both genic and hormonal factors. A single gene difference leads to divergent reactions to hormone in two races, Campines and Brown leghorns (610).

Henry Trendley Dean (US), Frederick S. McKay (US), and Elias Elvove (US) made a critical discovery. Namely, fluoride levels of up to 1.0 ppm in drinking water did not cause enamel fluorosis in most people and only mild enamel fluorosis in a small percentage of people (634).

Henry Trendley Dean (US), Francis A. Arnold, Jr. (US), and Elias Elvove (US) performed a statistical survey, which confirmed that the incidence of dental caries is significantly lower in communities where the water contains fluorine above certain concentrations (633).

In 1945, Grand Rapids, MI became the first city in the world to intentionally fluoridate its drinking water. During the 15-year project, researchers monitored the rate of tooth decay among Grand Rapids' almost 30,000 schoolchildren. After just 11 years, Francis A. Arnold, Jr. (US), Henry Trendley Dean (US), Philip Jay (US), and John W. Knutson (US) announced an amazing finding. The caries rate among Grand Rapids children born after fluoride was added to the water supply dropped more than 60 percent (71, 632).

Bernardo Alberto Houssay (AR) and Alfredo Biasotti (AR) removed the anterior lobe of the pituitary gland and pancreas from animals. They showed that the anterior lobe of the pituitary gland affects the course of sugar metabolism in the human. The anterior lobe seemed to produce one hormone that had the opposite effect of insulin (1292-1295). Their work explained spontaneous remission ofdiabetes mellitus – vanishing diabetes – by a destructive lesion in, or surgical removal of, the anterior pituitary gland.

József Baló (AT-HU) was the first to describe this phenomenon (vanishing diabetes) in humans (118).

Arnold Rice Rich (US) separated jaundice into two types on the basis of pathogenesis. The first, retention jaundice, results from the overproduction of the bile pigment in conditions that are associated with a decrease in excretory power of the liver, such as fever, anoxemia, and immaturity. The second type—regurgitation jaundice—is caused by reflux of bile from the liver canaliculi into the blood stream in the presence of duct obstruction or liver cell necrosis (2224).

Arnold Rice Rich (US) demonstrated that acquired resistance in the host is independent of the hypersensitive inflammatory reaction, and the latter, injurious to the host, may be eliminated by desensitization without impairment of immunity (2225, 2227).

Alexander A. Maximow (RU-US) posthumously authored A Textbook of Histology, which was one of the most influential histology texts of the twentieth century (1803). After Maximow’s death his book was completed and edited by William Bloom (US).

Anton Elschnig (AT) developed the method of corneal grafting introduced by Eugen von Hippel (DE) and produced good results on the human eye (817).

Magnus Hirschfield (DE) was the first true sex change pioneer. He coined the word transsexualism and founded, in Berlin, the first sexology institute. It was here that the first complete male-to-female sex change operation was performed in 1930. The patient was a Danish painter, Einer Wegener-Andreas Sparre, who had his genital organs removed, ovaries transplanted into him, and attempts made to furnish him with an artificial vagina. He died as a result of the series of operations, but before his death his marriage was annulled by the Danish authorities, who issued him a new birth certificate as a female, with the name Lili Elbe (804).

Louis Wolff (US), John Parkinson (GB), and Paul Dudley White (US) discovered what became known as the WPW (Wolff-Parkinson-White) Syndrome. This is a bundle-branch block with short P-R interval in healthy young people prone to paroxysmal tachycardia (3049).

Tetsuzo Akutsu (JP) and Willem Johan Kolff (NL-US) reported the development of a totally artificial heart in an animal model. They implanted a totally artificial heart into a living dog that subsequently survived for 90 minutes (18).

Lyle D. Joyce (US), Willem C. DeVries (US), W. Larry Hastings (US), Don B. Olsen (US), Robert K. Jarvik (US), and Willem Johan Kolff (NL-US) reported on the response of the human body to the first permanent implant of the Jarvik-7 Total Artificial Heart. In 1982, the heart was implanted into Barney Clark who lived 112 days following the implantation (1377).

The United States Congress passed the Plant Protection Act (PPA), which provided for the patenting of asexually reproducing varieties. In 1970, the Plant Variety Protection Act (PVPA) was extended to include breeder’s rights to sexually reproducing varieties.

Sydney Savory Buckman (GB), published dozens of papers on ammonites, named hundreds of them, and invented a new way of dating rocks by time zones called hemera, each with their characteristic ammonites. His hemeral scheme for the Jurassic Period contained 370 hemera and 47 ages, the latter roughly corresponding to Oppel's sediment Zones (334).

1931

“Concern for man himself and his fate must always be the chief interest of all technical endeavors … in order that the creations of the mind shall be a blessing and not a curse to mankind. Never forget this, in the midst of your diagrams and equations.” Albert Einstein (803).

Otto Heinrich Warburg (DE) was awarded the Nobel Prize in Physiology or Medicine for his discovery of the nature and mode of action of the respiratory enzyme (Atmungsferment); a system of cytochromes and their oxidases that participate in the respiratory process; often, specifically, cytochrome oxidase.

William Joseph Elford (GB) and Christopher H. Andrewes (GB) developed the first filters (graded collodion membranes) in which pore size could be precisely determined. They used these to determine that viruses range in size from large protein molecules to tiny bacteria (806, 807).

Linus Carl Pauling published his first essays on The Nature of the Chemical Bond, detailing the rules of covalent bonding (2049).

Jane Yip (US) and Loris A. Chahl (GB) found that Substance P and the NK1 receptor are widely distributed in the brain and are found in brain regions that are specific to regulating emotion (hypothalamus, amygdala, and the periaqueductal gray) (3088).

Otto Heinrich Warburg (DE) and Walter Christian (DE), and Alfred Griese (DE) found that adenine, nicotinamide, pentose, and phosphate were present in the ratio 1:1:2:3 in what was being called co-ferment or cozymase. They began referring to it as hydrogen-transporting co-ferment and stated, “The pyridine component of the co-ferment is its active group, because the catalytic action of the co-ferment depends on the alteration of the oxidation state of the pyridine part” (2897, 2900, 2901, 2907, 2908). It was called Wasserstoffübertragendes Co-ferment or hydrogen transport coenzyme then later referred to as triphosphopyridine nucleotide (TPN) then finally nicotinamide adenine dinucleotide phosphate (NADP) or coenzyme II. The location of the third phosphate was established after 1950 in the laboratory of Arthur J. Kornberg (US).

Adolf Friedrich Johann Butenandt (DE) and Kurt Tscherning (DE) isolated, crystallized, and identified androsterone (andro = male, ster = sterol, one = ketone) from male urine. They presented this discovery at a Hamburg chemical meeting on October 23, 1931.Using microanalysis techniques they were able to learn enough about it to predict its structure and draw up the full constitutional formula (373). Androsterone is now called testosterone.

Adolf Friedrich Johann Butenandt (DE), Günter Hanish (DE), Leopold Stefan Ruzicka (HR-CH), and Albert Wettstein (CH) partly synthesized the sex hormone testosterone from cholesterol (371, 372, 2334-2336). This was the first synthesis of a sex hormone and the first proof of the relationship between cholesterol and sex hormones.

Ernst Friedheim (CH-US) and Leonor Michaelis (DE-US) found that at acidic pH values, the oxidation-reduction of the natural pigment pyocyanine involves the step-wise transfer of one electron, with the intermediate formation of a free radical, which Michaelis termed a semiquinone (954).

Edgar Douglas Adrian (GB) and Frederik Buytendijk (NL) may be the first to present direct evidence that the brainstem contains all the neural elements necessary to generate breathing. Their experimental subject was the goldfish. They found that the rhythmic activity of the respiratory center in the goldfish could occur in the entire absence of sensory impulses (15).

Otto Fritz Meyerhof (DE-US) and Karl Lohmann (DE) stated that the role of adenylpyrophosphate (ATP), “ … appears to consist in the fact that the esterification of phosphate, which precedes the cleavage of carbohydrate to lactic acid, occurs with the simultaneous cleavage of adenylpyrophosphate, which is resynthesized during the further cleavage [of carbohydrate]. In this manner, the adenylpyrophosphate cycle maintains the lactic acid formation. The synthesis of phosphagen (creatine phosphate) is therefore made possible … by the cleavage energy of the adenylpyrophosphate, while the energy of lactic acid formation (from phosphate esters) serves to resynthesize the cleaved pyrophosphate” (1877).

Cornelis Bernardus Kees van Niel (NL), after elucidating the nature of bacterial photosynthesis, proposed that bacterial and plant photosynthesis are special cases of a general process in which light energy is used to photodecompose a hydrogen donor, H2A, with the released hydrogen in turn reducing carbon dioxide by dark, enzymatic reactions. The hypothesis envisaged that in plant photosynthesis H2A is water, whereas in green sulfur bacteria, e.g., H2A is H2S, with the results that oxygen becomes the by-product of plant photosynthesis and elemental sulfur the by-product of bacterial photosynthesis (2783-2785).

Keita Shibata (JP), in 1931, independently proposed the photo dissociation of water during oxygenic photosynthesis and a metabolism of anoxygenic photosynthetic bacteria very similar to the scheme proposed by van Niel (2477).

Heinz Ohle (DE) postulated that the anaerobic breakdown of glucose begins with its phosphorylation to glucose-6-phosphate, which is converted into fructose-1, 6-diphosphate (via fructose-6-phosphate); the hexose diphosphate was considered to undergo a series of oxidations and reductions leading to the formation of glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (2006).

Bishop C. Hsien Wu (CN) proposed that in addition to peptide covalent linkages between amino acids the native organization of proteins was due mainly to polar groups (3086).

Alfred Ezra Mirsky (US) and Linus Carl Pauling (US) stated, “Our conception of a native protein molecule (showing specific properties) is the following: The molecule consists of one polypeptide chain which continues without interruption throughout the molecule (or in certain cases, of two or more such chains); this chain is folded into a uniquely defined configuration, in which it is held by hydrogen bonds between the peptide nitrogen and oxygen atoms and also between the free amino and carboxyl groups of the diamino and dicarboxyl amino acid residues…. The characteristic specific properties of native proteins we attribute to their uniquely defined configuration. The denatured protein molecule we consider to be characterized by the absence of a uniquely defined configuration” (1897).

Walter J. Kauzmann (US) concluded that the most important energetic driving force behind the three-dimensional structure of proteins is a hydrophobic bond (1414).

Albert Jan Kluyver (NL) in his treatise, The Chemical Activities of Microorganisms, recognized the potential significance of the ideas that Neuberg, Wieland, Warburg, Harden, and a few others had advanced to account for more or less specific biochemical events. Soon it became evident to him that these concepts could be welded together into a very few general principles, applicable to all biochemical phenomena. The most basic of these generalizations is the extension of the ideas of Neuberg and of Wieland to their ultimate limits. Thus, any biochemical process, whether oxidation, fermentation, or synthetic reaction, was considered as a chain of step reactions, each one of which represented a simple mechanism in which hydrogen is transferred from one molecule, the H-donor, to another, the H-acceptor. The apparent exception to this principle was exhibited in the metabolism of complex molecules, composed of a number of simple entities, for example the polysaccharides (complexes of simple sugars), proteins (complexes of amino acids), and fats (complexes of fatty acids and glycerol). Such complexes would first be converted to their constituent units by hydrolytic cleavages, with the products subsequently undergoing the various hydrogen-transfer reactions. In this manner the existence of the many hydrolytic enzymes—glucosidases, proteinases, lipases, etc.—could be fitted into the general picture.

He advocated the use of microorganisms for comparative biochemical studies because of the ease of handling them under controlled and reproducible conditions, and because of the enormous biochemical versatility encountered within this group. It is often possible to select a specific microorganism as singularly appropriate for a given problem because it carries out a certain type of reaction to the exclusion of almost any other. But it is equally important to realize that one may find among these creatures the best examples of seemingly quite different biochemical properties with respect to the conversion of a particular substrate.

The recognition of this unity at the molecular level is Kluyver’s great contribution; it is also the starting point of comparative biochemistry (1465).

Johann Heinrich Emil Heitz (DE) and Barbara McClintock (US) demonstrated that the nucleolus in somatic cells is regularly associated with a particular locus on one or more chromosomes. McClintock defined this region as the nucleolar organizer (1205, 1818).

Donald M. Wilson (GB) explored the control of rhythmic locomotion of flight mechanics in the desert locust Schistocerca gregaria. He provided evidence to reject the proprioceptive chain reflex model by rigorously demonstrating that the full motor pattern of locust flight could be generated by fully deafferented thoracic ganglia, which could not receive the inputs required by the proprioceptive chain model. He proposed that ‘the basic co-ordination of flight is an inherent function of the central nervous system but that peripheral feedback loops influence the frequency of operation and details of pattern' (3025).

Keir G. Pearson (CA) and John F. Iles (CA) focused on the hind legs of the cockroach Periplaneta americana and, in particular, on a subset of the muscles that raise (levate) and lower (depress) the limbs during the swing and stance movements of a step cycle, respectively. They demonstrated for the first time that alternating patterns of levator and depressor motor activity similar to those seen in walking were generated centrally in the absence of leg sensory feedback. Put simply, the basic motor pattern was generated within the central nervous system (2058).

Keir G. Pearson (CA) confirmed the work in the 1970 paper then went on to provide strong evidence that sensory feedback acted to modify the centrally generated pattern of activity (2057).

Donald M. Wilson (GB) emphasized the corrective role of sensory feedback: ‘the importance of sensory feedback in behavior patterns appears not to lie in the cueing of sequences but rather in the correction of errors inherent in genetically determined motor programs’ (3026).

John Charles Walker (US) developed and released peas resistant to Fusariumwilt and near-wilt disease (2882).

Karl Friedrich Meyer (US), Clarence M. Haring (US), and Beatrice Howitt (US) isolated the virus of Western equine encephalomyelitis from the brains of infected horses during an outbreak in California (1857, 1858).

Wilbur A. Sawyer (US) and Wray Lloyd (US) developed a Serum Neutralization Test for the presence of yellow fever (2373).

Wilber A. Sawyer (US), Stuart F. Kitchen (US), and Wray Lloyd (US) developed a vaccine to yellow fever using the attenuated virus. The vaccine had two parts: a ten-percent suspension of mouse-brain tissue with yellow fever virus in fresh sterile human serum, and human immune serum from people recently recovered from yellow fever (2372).

Alice Miles Woodruff (US) and Ernest William Goodpasture (US) developed the first practical method for cultivating large quantities of a virus in the laboratory—by growing it on the exposed membrane of a chick embryo (3061).

Charles E. Clifton (US), Edwin William Schultz (US), and Louis P. Gebhardt (US) used ultrafiltration collodion membranes to estimate that poliomyelitis virus is less than 50 nanometers in diameter (486). Subsequent work by them placed its size at close to 25 nanometers.

Richard E. Shope (US) and Paul A. Lewis (US) found that two infectious agents are necessary to induce the most severe form of swine influenza, the influenza virus and a bacterium he called Haemophilus influenzae suis. The virus alone produced a mild form of the disease (1653, 2480, 2481). He later speculated that survival of the virus during inter-epidemic periods involves virus persisting in a latent form in the parasitic pulmonary nematode (lung worm) of the pig. The virus is incorporated in the ova of the nematode, which is later eaten by an earthworm that serves as its intermediate host. After the lung worm reaches a certain stage of development the earthworm is eaten by the pig and influenza virus inside the nematode returns to the lungs of the same or another pig (2484, 2488, 2491-2493).

Robert Daubney (GB), J.R. Hudson (GB), and Percy Cyril Claude Garnham (GB) were the first to isolate the Rift Valley fever virus (RVFV), a type of bunyavirus (Phlebovirus). They found it in East African sheep (614).

Sara E. Branham (US), Clara Enola Taft (US), and Sadie A. Carlin (US) identified a new organism, Neisseria flavescens, as a rare cause of meningitis and septicemia in humans, but one requiring careful differentiation from meningococcus (279, 280). In 1970 Branham was honored posthumously by the name of a new genus, Branhamella.

Ernst Lowenstein (DE) and Kai Adolf Jensen (DK) developed a culture medium for the isolation and cultivation of mycobacteria and as bases for selective, differential, and enriched media for mycobacteria. Malachite green is used to inhibit non-mycobacterial organisms (1361, 1713).

J.S. Anderson (GB), Frank C. Happold (GB), James Walter McLeod (GB), and J.G. Thomson (GB) discovered that severe cases of diphtheria were nearly always caused by a genetic variety of Corynebacterium diphtheriae referred to as gravis. The mild cases were usually associated with the variety called mitis. The two varieties were easily distinguishable from one another because of their characteristic colonies formed on solid media (54).

A.S. Michailoff (DE) was the first to report on a mutation in the honeybee, Apis mellifera Linn. It was the ivory eye color which he referred to as white (1886).

Harriet B. Creighton (US) and Barbara McClintock (US), working with corn (Zea mays), obtained cytological proof that the inheritance of novel gene combinations during crossing over is due to the physical exchange of specific chromosome segments (567).

Curt Stern (DE-US), using cytologically abnormal X-chromosomes of Drosophila, one with the X-Y translocation, and one with an X-IV translocation, demonstrated that the genetic phenomenon of crossing over is accompanied by a physical exchange between the chromosomes (2629). See, Janssens, 1909.

P. Zhivago (RU), B. Morosov (RU), and A. Ivanickaya (RU) discovered that a much better spread of chromosomes occurs if water is used instead of isotonic solutions during the preparation of a chromosome squash (3098).

Sewall Wright (US) presented the first unified picture of evolution in terms of Mendelism by illustrating the relations between selection pressure, mutation rates, inbreeding, and isolation (3084).

Leonard H. Snyder (US) and Albert Francis Blakeslee (US), based on experiments using phenyl thiocarbamide (PTC), concluded that tasting is inherited as a Mendelian recessive trait, with "taste" being dominant to "non-taste." In addition Blakeslee showed that there is a threshold concentration below which "tasters" cannot detect PTC (218, 2550).

John Punnett Peters (US) and Donald Dexter van Slyke (US) wrote the two volume Quantitative Clinical Chemistry, for many years the world authority (2082, 2083).

Leopold Heine (DE) performed work, which made the manufacture of modern contact glasses possible (1203).

Philip Duryeé McMaster (US) and Stephen S. Hudack (US) proved that lymphatics instead of being passive drainage canals are very active in the process of fluid exchange. Their walls respond rapidly to various influences such as sunlight, warmth, or a state of shock that does not break the skin (1309-1313, 1827-1829).

António Caetano Abreau Freire De Egas Moniz (PT) conceived visualization of cerebral blood vessels by röntgenography. The medium he developed with comparative safety used sodium iodide. When colloidal thorium dioxide was developed he followed up this lead with cerebral angiography to visualize intracranial tumor, vascular abnormalities, and aneurysms (791, 792).

Harvey Williams Cushing (US) removed a pituitary tumor from a patient on April 15, 1931. This was the 2000th verified brain tumor removed by Cushing in his remarkable career during which he reduced the mortality rate in brain surgery from more than 90 percent to a little over 8 percent. Cushing operated for an additional fifteen months before retiring (2244). In a supreme irony he died in 1939 of a brain tumor.

Harvey Williams Cushing (US) reported on the surgical-mortality percentages pertaining to the two thousand operations he had performed for the removal of intracranial tumors (581).

Christian Georg Schmorl (DE) established the modern basis for understanding the intervertebral disc, by providing very clear discussions of herniations as well as degenerations (2394).

James Rognvald Learmonth (IR) observed that if the hypogastric nerve is stimulated the result is contraction of the ipsilateral ureteral orifice; tightening of the trigone; contraction of the internal sphincter; and contraction of the musculature of the prostate, seminal vesicles and ejaculatory ducts. Sectioning the hypogastric nerve produces relaxation of the ureteral orifice, trigone and internal sphincter, with no appreciable effect on the dome or lateral walls of the bladder (1610).

Derek Ernest Denny-Brown (NZ-GB-US), E. Graeme Robertson (AU), and Alex E. Roche (GB) studied the events of voiding and the volumetric changes of the bladder in relation to sphincter activity. They found spontaneous waves of pressure in the bladder during filling. As these increased in amplitude, subjective sensations of fullness or urinary urgency developed in the subjects. The subjects, when asked, could voluntarily suppress the summation of these pressure waves (670-672).

Michael S. Burman (US) carried out the first extensive academic research in arthroscope usage in the United States. Arthroscopy being the direct visualization of joints (346).

Paul Dudley White (US) virtually created the specialty of cardiology in the United States when he published his book, Heart Disease (2968).

Another outbreak of polio swept the U.S. during the summer of 1931, killing more than 4,000 people, about 12 percent of the reported cases (1482).

George Gaylord Simpson (US) united the two families of anthropoid apes, Pongidae (Simiidae), and men, Hominidae, into a Superfamily, which he called Hominoidea, and distinguished from the two other superfamilies of the sub-order Anthropoidea, which he called the Cercopithecoidea and the Ceboidea. The superfamily Hominoidea includes the hominoids (gibbons, great apes, and humans). The term hominid refers only to humans (2506).

Marius Pièry (FR), Julien Roshem (FR), and Vilhelm Moller-Christensen (DK) gave accounts of Stone Age homonoid skeletons diagnosed as exhibiting signs of tubercular damage. Evidence of pulmonary tuberculosis remains but, in the nature of the case, it is meager (1905, 2099).

Erik Andersson Stensiö (SE) and Gunnar Säve-Söderbergh (SE), of the 1929-1930 Danish scientific expeditions, found ichthyostegid fossils in the upper Devonian sediments in eastern Greenland. They appear to be intermediate between lobe-finned rhipidistians (Osteolepis) and early amphibians. These are the oldest known fossils that can be classified as amphibians (2369, 2627).

Arthur Tindell Hopwood (GB), in 1931, discovered the fossils of three hominids near Lake Victoria, he would name them Proconsul in 1933 (1273, 1274). This was the oldest known ape found up to this time.

Wilfred E. Le Gros Clark (GB) and Louis Seymour Bazett Leakey (GB-KE), reported on a hominid skull and jaw found by Mary Douglas Nicol Leakey (GB-KE), in 1948, in Miocene deposits on Rusinga Island in Lake Victoria, Western Kenya. It was an excellent sample of Proconsul africanus (sometimes called Dryopithicus africanus or "woodland ape"). The specimen is approximately 16 million years old. Proconsul is a candidate for the distant ancestor from which all modern species of apes and all hominids—human beings included—evolved.

1932

“If a patient is poor he is committed to a public hospital as psychotic; if he can afford the luxury of a private sanatorium, he is put there with the diagnosis of neurasthenia; if he is wealthy enough to be isolated in his own home under constant watch of nurses and physicians he is simply an indisposed eccentric.” Pierre Marie Félix Janet (1356).

Charles Scott Sherrington (GB) and Edgar Douglas Adrian (GB) were awarded the Nobel Prize in Physiology or Medicine for their discoveries regarding the functions of neurons.

Harold Clayton Urey (US), Ferdinand G. Brickwedde (US), and George M. Murphy (US) were the first to prove that hydrogen gas contains a few atoms in which the nuclear proton is accompanied by a neutron. This so called heavy hydrogen was given the name deuterium (2766, 2767).

Sigmund Otto Rosenheim (GB) and Harold King (GB) worked out the correct structure for the rings found in bile acids and sterols (including cholesterol) (2299-2302).

Cecil James Watson (US) crystallized stercobilin from human feces and proved that it is different from urobilinogen and mesobilirubinogen. In the process he discovered mesobiliviolin in nature for the first time (2916).

Joseph K. Tillmans (DE), Paul Hirsch (DE), and Johannes Jackisch (DE) were the first to introduce a quantitative chemical test for the presence of vitamin C. If was based on the relationship between the vitamin C content of a food and its reducing power (2726).

Robert Emerson (US) and William A. Arnold (US) articulated the concept of a photosynthetic unit (photosystem), which includes the two components, antenna and reaction center (825, 826).

Robert F. Parker (US) and Ralph S. Muckenfuss (US) adapted the Complement Fixation Test for the detection of smallpox antigen in lesion fluid. This represents the first immunological test for viral antigens (2038).

Max Schlesinger (DE-GB) used the adsorption capacity of the bacterial cell for bacteriophages and the sedimentation velocity of bacteriophages to determine that the bacteriophage particle has a maximum linear dimension of about 0.1 micrometer and a mass of about 4 x 10-16 g. His studies of the kinetics of bacteriophage attachment imply that Brownian movement brings bacteriophage particles into random collisions with the bacterial surface. He purified a weighable amount of T-even bacteriophage by differential centrifugation and graded filtration; then by direct chemical analysis found that they consisted mainly of protein and DNA, in roughly equal proportions (2384-2386).

Max Bergmann (DE-US) and Leonidas Zervas (DE-US) developed a method for synthesis of polypeptides, which was superior to the Fischer synthesis because it allowed the inclusion of complex amino acids in the polymer (187).

Otto Heinrich Warburg (DE) and Walter Christian (DE) isolated, from yeast, a yellow-red protein which they called oxygen-transporting-ferment and concluded that, “The yellow ferment is therefore not only an oxygen-transporting ferment but also a ferment of oxygen-less respiration. … It is probable that in life, the yellow ferment does not transfer molecular, but bound oxygen. Probably, in life, it is not an oxygen-transporting ferment but an oxidation-reduction ferment.” They went on to show that the pigment is a small molecule, which is released when the protein portion of the complex is denatured. The pigment was found to belong to the class of substances that Richard Johann Kuhn (AT-DE) had named flavins (2898, 2899).

Axel Hugo Theodor Theorell (SE) showed that the coenzyme associated with Warburg’s yellow enzyme had a structure like riboflavin (vitamin B2), to which a phosphate group was attached (2709).

Richard Johann Kuhn (AT-DE), Hermann Rudy (DE), and Friedrich Weygand (DE) found that the active form had a phosphate group at the five prime position (vitamin B2 is riboflavin phosphate or flavin mononucleotide) and behaves as a prosthetic group carrying out its catalytic function while complexed with protein as a flavoprotein (1540).

Joachim Hämmerling (DE) performed a series of classic experiments using the alga Acetabularia spp. as his material. He concluded that there must be intermediate stages between the genetic information of the cell nucleus and expression of the genetic information in the cytoplasm. Furthermore these intermediate stages must be represented by chemically defined substances (m-RNA), which were called morphogenetic substances, and even in darkness the nucleus continues to supply the cytoplasm with morphogenetic substances. In the 1934 reference Hämmerling found that chloroplasts divide in anucleate cells (1140-1146). Note: This work is remarkable as a harbinger of molecular biology.

Hans Adolf Krebs (DE-GB) and Kurt Henseleit (DE) worked out the way in which the body eliminates waste nitrogen, usually from deamination reactions, by breakdown and regeneration of a portion of the amino acid arginine. This urea cycle (or ornithine cycle), as it is called, ultimately leads to the excretion of waste nitrogen as urea. In their own words, “The primary reaction of urea synthesis in the liver is the addition of one molecule of ammonia and one molecule of carbonic acid to the d-amino group of ornithine, with the elimination of one molecule of water and the formation of a d-ureido acid, citrulline … The second reaction of urea synthesis is the combination of one molecule of citrulline with an additional molecule of ammonia, with the loss of a second molecule of water and the formation of a guanidino acid, arginine … The third reaction is the hydrolytic cleavage of arginine to ornithine and urea” (1519-1521).

V. Albrecht Bethe (DE) introduced the concept of ectohormones, now known as pheromones (204). See Karlson, 1959. One member of a species to affect the physiology or behavior of another member of the same species excretes these chemicals.

Carl Vincent Smythe (DE) and Waltraut Gerischer (DE), in 1933, showed that yeast could ferment DL-glyceraldehyde-3-phosphate, consuming only one of the isomers (2545). Later work showed that it was the D isomer being metabolized.

Marcus Morton Rhoades (US) demonstrated in maize that crossing over among chromosomes occurs at the four-strand stage (2220).

Franz Schrader (DE-US) concluded that spindles in living cells do indeed have a fibrous structure, albeit an invisible one. In bipolar spindles he described these fibrous arrays as consisting of: 1) those running from a spindle pole to each chromosome or chromatid, namely, chromosomal fibers or half-spindle components; 2) continuous fiber systems from pole to pole; and, in some organisms 3) interzonal fibers of quite different nature connecting the ends of separating chromatids at anaphase (2420, 2421).

William Henry Chandler (US), Dennis Robert Hoagland (US), and Paul Llewellyn Hibbard (US) discovered that zinc deficiency causes a number of physiological disorders in plants, including little leaf in peaches, mottle leaf in citrus, and rosette in apples (435).

Howard S. Reed (US) and Jean Dufrenoy (US) described the signs and symptoms of zinc deficiency in plants (2206).

Richard Edwin Shope (US) showed that mad itch, a violent, distressing, and fatal disease of cattle in the American Midwest is caused by a virus transmissible to rabbits, and endemic among pigs. He identified mad itch as being identical to pseudorabies in Europe (2483).

Richard Edwin Shope (US) discovered the viral etiology of rabbit fibroma disease found in wild cotton tail rabbits (Sylvilagus) in the United States (2482, 2485-2487, 2490). This is often called Shope fibroma.

Francis Peyton Rous (US), and Joseph W. Beard (US) successfully induced a tumor in mammals using a virus. The virus causes a papilloma in rabbits. Today it is called the Shope papilloma virus (2305, 2306).

Chester Hamlin Werkman (US) and George Francis Gillen (US) proposed the bacterial generic term Citrobacter for the citrate-positive, coli-aerogenes intermediates, with Citrobacter freundii Braak as the type species (2946).

Carl Clarence Lindegren (US) worked out much of the basic genetics of the fungus, Neurospora (1676).

Margaret Newton (CA-US) and Thorvaldur Johnson (CA) developed techniques to allow them to hybridize the rust fungus while it grew on barberry. They discovered that pathogenic characters segregated in a Mendelian fashion while some other characters appeared to be inherited in a maternal pattern (1367, 1368, 1981, 1982).

Helmuth Weese (DE) and Walther Scharpff (DE) reported on their first experiences with hexobarbital (the first short-acting barbiturate) for intravenous induction of general anesthesia. It is also called evipan and evipal (2929).

Eliot R. Clark (US) and Eleanor Linton Clark (US) placed glass-windowed chambers in the rabbit ear and made exquisite drawings of the branching patterns of the blood vessels that entered the wound. Their work established the field of vascular biology (464).

Philip Duryeé McMaster (US), Stephen S. Hudack (US), and Francis Peyton Rous (US) found that there is a relation of hydrostatic pressure to the gradient of capillary permeability (1832).

James Augustine Shannon (US), Norman Jolliffee (US), Homer W. Smith (US), and Saul Fisher (US), in their studies of the kidney, developed a way to precisely measure the rate of formation of glomerular filtrate (i.e., the volume per unit time of plasma ultrafiltrate that, under the hydrostatic pressure in the arterial circulation, enters the kidney tubules and flows toward the urinary bladder) in a variety of species—amphibians, reptiles, birds, and mammals, including Homo sapiens. They went on to illuminate passive reabsorption from tubular lumen back across the tubular epithelium to the peritubular blood, simple diffusion along a chemical concentration gradient of urea created by the reabsorption of water, active reabsorption, and active secretion (1374, 2445-2452, 2454-2456). See, Eli Kennerly Marshall, Jr., 1923, and Joseph Treloar Wearn, 1924.

James Augustine Shannon (US), Saul J. Farber (US), and Leonard Troast (US) determined the transport maximum (Tm) for glucose in the normal dog kidney tubule. The value was found to be stable over months and not influenced by blood levels of glucose or insulin. They proposed that it be used as a marker of reabsorption capacity (2453).

Allen Dudley Keller (US) and William Kendrick Hare (US) gave the heat regulating function of the brain a more precise location in the hypothalamus (1423).

James Gray (GB) produced three papers, which represent the cornerstone of our understanding of aquatic locomotion by animals (1072-1074).

Marius von Senden (DE) reported that if congenital cataracts in children were removed then replaced by glass lenses the return to vision was long and arduous even though the retina seemed perfectly normal. Return to normal vision was exceptional (2842, 2843).

Alfred Bielschowsky (DE-US) wrote Die Lähmungen der Augenmuskeln, a standard work on motility disturbances of the muscles of the eye (205).

Edgar Alphonso Hines, Jr. (US) and George Elgie Brown (US) introduced a test designed to detect latent states of hypertension (1238). It became known as the Hines-Brown Test.

Albert S. Hyman (US) is credited with originating the concept of the artificial heart pacemaker. He stimulated the heart in animal experiments by inserting a transthoracic needle into the right ventricle, the other end of which was attached to a mechano-electrical pacemaker. He later employed the same technique in a human patient (1327).

John Alexander Hopps (CA) devised a cardiac pacemaker. Hopps was trained as an electrical engineer at the University of Manitoba and joined the National Research Council in 1941, where he conducted research on hypothermia. While experimenting with radio frequency heating to restore body temperature, Hopps made an unexpected discovery: if a heart stopped beating due to cooling, it could be started again by artificial stimulation using mechanical or electric means.

Wilfred Gordon Bigelow (CA), John C. Callaghan (CA), and John Alexander Hopps (CA) developed and tested the first artificial cardiac pacemaker for human use (206, 387). This device was far too large to be implanted inside of the human body. It was an external pacemaker.

Paul Maurice Zoll (US) used the application of electric stimuli from an artificial external cardiac pacemaker by way of subcutaneous needle electrodes to produce effective ventricular beats in 2 patients with ventricular standstill after complete heart block (3107). Some consider this the invention of the cardiac pacemaker. Dr. Zoll's later studies showed that externally applied, alternating current counter shocks are similarly effective in stopping ventricular fibrillation, and also in correcting a number of other serious, potentially lethal, abnormalities of rhythm. He developed the theory and technique of continuous cardiac monitoring of heart rhythm, and was the first to apply this method clinically.

Earl E. Bakken (US), in 1957, at the suggestion of Clarence Walton Lillehei (US) developed the world's first transistorized, battery-powered, external, wearable cardiac pacemaker. Very shortly thereafter Clarence Walton Lillehei (US), Vincent L. Gott (US), Paul Chesley Hodges (US), and David M. Long (US) installed this pacemaker on a patient to treat complete atrioventricular dissociation (1673). This gave patients mobility and eliminated concerns about a power failure. Bakken later formed the Medtronics Corporation which developed the first fully implantable, self-contained, transistorized, wearable, battery operated pacemaker in 1960.

Rune Elmquist (SE) developed the first fully implantable pacemaker. Ake Senning (SE), on 10/8/1958, implanted this devise into Arne H.W. Larsson (SE) who suffered from up to twenty fainting attacks per day (816). Mr. Larsson died on 12/38/2001.

William Chardack (US), Andrew Gage (US), and Wilson Greatbatch (US), devised a workable transistorized, implantable, pacemaker using primary cells as a power source. It was known as the Chardack-Greatbatch implantable pacemaker. It was the first to be implanted in a patient with AV block (1077).

Yves Bouvrain (FR) and Fred I. Zacouto (FR) described a combination of devices they called a “resuscitation device”. This consisted of a heart monitor, a defibrillator, and a pacemaker (264).

Orestes Fiandra (UY) and Roberto Rubio (UY), in February 1960, inserted a totally implantable pacemaker into a 34-year-old patient with AV block. Its battery life was approximately 12-18 months (894).

Philippe Coumel (FR), Christian Cabrol (FR), Alexandre Fabiato (US), René Gourgon (FR), and Robert D. Slama (US) used programmed atrial and ventricular stimulation to unravel the mechanism and diagnosis of permanent junctional reciprocating tachycardia in a drug-refractory patient. They showed that tachycardia was sustained by a reentrant or reciprocal rhythm, then postulated that the process involved dual AV nodal pathways with a slow conducting retrograde pathway. They installed a permanent bipolar pacemaker in such a way as to relieve the tachycardia (558).

John Burdon Sanderson Haldane (GB) points out the importance of knowledge about the age/stage of gene expression - gametophytes and gametes to zygotes, embryos and immature and mature organisms in evolutionary studies (1126).

1933

“If all the arts aspire to the condition of music, all the sciences aspire to the condition of mathematics.” George Santayana (2364).

“It is common sense to take a method and try it. If it fails, admit it frankly, and try another. But by all means, try something.” Franklin D. Roosevelt, Fireside Chat, March 12, 1933.

Thomas Hunt Morgan (US) was awarded the Nobel Prize in Physiology or Medicine for his discoveries concerning the role played by the chromosome in heredity.

Georges Edouard Lemaitre (BE) proposed the Big Bang theory of the origin of the universe. He visualized a primal atom, an incredibly dense egg containing all the material for the universe within a sphere about 30 times larger than the Sun. This primal atom exploded some 20-60 Ga scattering matter and energy in all directions (1625).

Niels Henrik David Bohr (DK) introduced the idea of complementarity to biology. All properties of physical entities exist only in pairs, which Bohr described as complementary or conjugate pairs (which are also Fourier transform pairs). Physical reality is determined and defined by manifestations of properties, which are limited by trade-offs between these complementary pairs (242).

John Desmond Bernal (GB) and Ralph Fowler (GB) created their model of the structure of liquid water (195).

John Desmond Bernal (GB) and Helen Dick Megaw (IE) introduced the notion that hydrogen atoms in bulk liquid water can jump in concerted fashion between the two oxygen atoms that they link together (197).

Dinitrophenol compound was introduced in France as a herbicide for the control of annual broadleaf weeds in cereals. ref

André Félix Boivin (FR) discovered that the somatic antigen (endotoxin) is present in all Enterobacteriaceae regardless of their pathogenicity (243).

Rudolf Schoenheimer (DE-US) and Fritz Breusch (DE-US) concluded that cholesterol is continually destroyed as well as formed in the animal body (2399).

Karl Lohmann (DE) discovered glucose-6-phosphate isomerase, one of the phosphoglucose enzymes, which were subsequently found to catalyze the breakdown of sugar phosphates according to the glycolytic scheme (1694).

Morna MacLeod (GB) and Robert Robison (GB) isolated fructose-1-phosphate from the partial hydrolysis of fructose diphosphate by bone phosphatase (1751).

William Smith Tillett (US) and Raymond L. Garner (US) found that certain strains of hemolytic streptococci produce a substance capable of inciting the rapid fibrinolysis of human plasma clots. They named the lytic agent fibrinolysin (996, 997, 2720). This represents the beginning of investigations of streptokinase.

Haskell Milstone (US) suggested that a plasma factor, which he called plasma lysing factor, is responsible for streptococcal mediated fibrinolysis (1894).

L. Royal Christensen (US) and Colin Munro MacLeod (US) were able to describe the entire mechanism of streptococcal fibrinolysis. They showed that human plasma contains the precursor of an enzyme system, which they called plasminogen, and that the streptococcal fibrinolysin, which they named streptokinase, is an activator which can convert plasminogen to the proteolytic and fibrinolytic enzyme plasmin (455-457).

Stuart D. Elliott (US) was the first to extract streptokinase and its proenzyme (zymogene) in the crystallized form (813).

Sol Sherry (US) started using streptokinase in patients with acute myocardial infarction and changed the focus of treatment from palliation to “cure” (2476).

Streptokinase (SK) has been used in medicine as fibrinolytic enzyme system - plasminogenous activator. SK is used for myocardial infarctions, vein thrombosis, lung artery emboly, occlusions of extremity arteries, retinal blood-vessel thrombosis and priapism.

Maurice W. Goldblatt (GB) and Ulf Svante Hansson von Euler-Chelpin (SE) independently discovered that extracts of human semen, monkey, sheep and goat seminal vesicular glands respectively cause contraction of smooth muscle in vitro and sharp decreases in the blood pressure in experimental animals (1038, 1039, 2831-2833). Von Euler-Chelpin called these substances prostaglandins because they were mistakenly believed to be made in the prostate gland.

Lárus Einarson (DK) suggested that the chromatic material of the Nissl Granules or Bodies in neurons is formed around the nucleolus and then diffuses out into the cytoplasm (800).

George Wald (US) found vitamin A (retinol) in the retina (2861, 2864).

George Wald (US) discovered retinene (retinal), an intermediate in the bleaching of rhodopsin, on the way to vitamin A (retinol). He concluded that rhodopsin in the retina, under the influence of light, engages in a cycle of reactions with retinene and vitamin A (2862, 2863).

George Wald (US) and Anna-Betty Clark (US) presented evidence that visual purple is a conjugated protein in which vitamin A (retinol) is a prosthetic group (2864, 2874).

George Wald (US) discovered that visual pigment from freshwater fish differs from that of mammals, birds, amphibia, and marine fish. He named it porphyropsin (2865, 2867).

George Wald (US), Paul K. Brown (US), and Patricia H. Smith (US) determined that all known visual pigments are built upon a common plan. Retinal is bound as chromatophore to a type of protein, called an opsin, found in the outer segments of vertebrate rods and cones and the analogous rhabdomeres of invertebrates. There are four major pigments known in vertebrate vision: 1) retinal 1 + rod opsin = rhodopsin, 2) retinal 1 + cone opsin = iodopsin, 3) retinal 2 + rod opsin = porphyropsin, and 4) retinal 2 + cone opsin = cyanopsin (2866, 2872, 2873).

George Wald (US) and Ruth Hubbard (US) demonstrated that the visible pigment (rhodopsin) from the cones of the eye contains a protein (opsin) in combination with retinene (retinal). Retinene is very similar in structure to vitamin A (retinol) and is formed from vitamin A in the body. When light strikes rhodopsin, the protein and the retinene separate; they recombine in the dark (1307, 2875).

Ruth Hubbard (US) and George Wald (US) identified the initial molecular event in vision by showing that when 11-cis retinal absorbs a photon, it is converted to the all-trans form (1308).

Paul K. Brown (US) and George Wald (US) demonstrated that two different proteins, two opsins, are needed to form the red- and green-sensitive pigments suggesting that two genes are involved in red- and green-blindness (315).

William B. Marks (US), William H. Dobelle (US), Edward F. MacNichol (US), Paul K. Brown (US), and George Wald (US) found that primate retinas possess, in addition to rod cells with their rhodopsin, three kinds of cone cells, blue-, green- and red sensitive, each containing predominantly or exclusively one of three color pigments with maximum absorption at 435, 540, and 565 micrometers respectively (316, 1774).

George Wald (US) predicted that light activated rhodopsin might trigger a cascade of reactions much like the blood clot cascade (2868).

George Wald (US) discovered the primary event in vision to be when light triggers visual excitation by isomerizing the 11-cis retinal chromophore of visual pigments to the all-trans form (2869-2871).

Moses Kunitz (RU-US) and John Howard Northrop (US) were the first to crystallize the enzyme chymotrypsin and its precursor chymotrypsinogen. They isolated and crystallized a new protein from the pancreas. It separated as elongated prisms and had no proteolytic action. However, when acted upon by a trace of active trypsin it was converted into a second protein, crystallizing in plates, which had a proteolytic activity about a third as great as crystalline trypsin-1. The new enzyme had less hydrolytic action on gelatin than trypsin-1, but had a powerful action on coagulating milk. They called the inactive form chymotrypsinogen and the trypsin activated form chymotrypsin (1546, 1547).They also isolated and crystallized trypsinogen, a trypsin inhibitor, and an inhibitor-trypsin compound (1548).

Fritz Kögl (NL) and Benno Tönnis (NL) isolated and crystallized a vitamin from the boiled yolks of duck eggs. They named it biotin (1479).

Paul György (HU-DE-GB-US) and Thomas William Birch (US) isolated a vitamin in pure form, which would cure raw egg white injury (harm done when raw egg whites are the sole protein source in a diet). They named it vitamin H (biotin) (209, 1116).

Dietrich Hans Franz Alexander Bodenstein (DE-US), working with caterpillars of the butterfly Vanessa urticae, concluded that the time course of molting is not determined by autonomous changes in the hypodermis, but rather that factors situated elsewhere within the caterpillar, most likely blood borne hormones, determine the time course of molting (239).

Evelyn Mary Anderson (CA) and James Bertram Collip (CA) were the first to successfully isolate a tropic substance. It was thyrotropic hormone (TSH) from the anterior pituitary gland (53).

James Bertram Collip (CA), Evelyn Mary Anderson (CA), and David Landsborough Thomson (GB-CA) prepared and tested extracts from the anterior pituitary gland and found that they contained a potent adrenotropic hormone (ACTH) (510).

Gustav Georg Embden (DE), Hans-Joachim Deuticke (DE), and Gert Kraft (DE) proposed that in muscle cell glycolysis, fructose-1, 6-diphosphate is cleaved directly to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate. These products were considered to undergo a Cannizzaro (mutase) reaction to yield 3-phosphoglycerol and 3-phosphoglyceric acid, and the latter was thought to be converted into pyruvic acid and phosphate. A second mutase reaction between pyruvic acid (which is reduced to lactic acid) and phosphoglycerol (which is oxidized to glyceraldehyde-3-phosphate) completed the balance of equations, and provided for the conversion of all the hexose into lactic acid (823).

Gustav Georg Embden (DE), Hans-Joachim Deuticke (DE), and Gert Kraft (DE) proposed a anaerobic glycolytic scheme within muscle cells which begins with the conversion of hexosediphosphate into triosephosphate which, by the oxidation reduction process, yields alpha-phosphoglycerol plus 3-phosphoglyceric acid; phosphoglyceric acid breaks down to pyruvic and phosphoric acids. In muscle extract, pyruvic acid is reduced to lactic acid at the expense of the phosphoglycerol, which is oxidized to triosephosphate. In yeast juice, pyruvic acid is converted by carboxylase into carbon dioxide plus acetylaldehyde. The latter was then believed to take part with glucose and inorganic phosphate in a rapid reaction in which hexosediphosphate plays the part of a catalyst and phosphorylation is coupled with an oxidation-reduction; the primary esterification product is oxidized to phosphoglyceric acid while the acetylaldehyde is reduced to alcohol (823). This evidence suggested that it is pyruvic rather than lactic acid which represents the true end product of anaerobic glycolysis.

Otto Fritz Meyerhof (DE-US) offered proof that, in isolated but otherwise intact frog muscle, the lactic acid formed is reconverted to carbohydrate in the presence of oxygen. He also prepared a KCl extract of muscle, which could carry out all the steps of glycolysis with added glycogen and hexose-diphosphate in the presence of hexokinase derived from yeast. In this system glucose was also glycolysed and this was the foundation of the Embden-Meyerhof-Parnas theory of glycolysis (glyco, sugar; glykis, sweet). The specific sequence of reactions from glucose to pyruvate is often called the Embden-Meyerhof-Parnas pathway (1871-1874). In the 1935c article give the first description of phosphoglyceric acid mutase (phosphoglycerate mutase).

Otto Fritz Meyerhof (DE-US) and Wilhelm Kiessling (DE) published a detailed study of the intermediary phases of fermentation in yeast juice (1869).

Otto Fritz Meyerhof (DE-US) worked out the chemical scheme of the cellular breakdown of sugar into alcohol (1861).

Ernst Wolfgang Caspari (DE-US), working with the flour moth Ephestia kuhniella Zeller, provided an example of how a gene can control hormone action during development (409, 410).

John Belling (GB-US) states that “ crossing over” exists apparently in all those flowering plants, which have been sufficiently investigated with regard to it. Billing’s modification of Janssens' hypothesis explains crossing over, and also explains gene rearrangements, such as reversed crossing over, reciprocal translocation, inversion, deletion, and deficiency. The chromonemas were proved to be unsplit at leptotene in certain plants. Living (and also fixed) chromonemas of resting “final” nuclei showed no split, in the plants examined. The secondary split was first seen at mid-pachytene. Both direct and oblique chiasmas were seen at pachytene in Lilium. After the chromomeres have split, the old longitudinal fibers are either alone visible; or are seen to be thicker than the new ones. In Lilium the opening-out at diplotene seems to be only at the primary split. In plants such as Datura, with no chiasmas at diaphase, it is probable that the diplotene opening-out alternates at the chiasmas. Since chiasmas arise at pachytene in certain liliaceous plants, they cannot arise from alternate opening-out at diplotene. Chiasmas seem to be due to overlaps, not twists. Overlaps may be sometimes mistaken for twists, under the microscope. There are 8 main kinds of double chiasmas, equally numerous by chance. Double chiasmas give, by chance, one non-crossover chromosome, two single-crossover chromosomes, and one double-crossover chromosome. If crossovers arise from chiasmas, then the distal recombinations from the end to the fusal chromomere should be 50 percent. If crossovers arise from chiasmas, then the chart crossovers divided by 50 should give the average number of chiasmas. The ascertained numbers of crossover X chromosomes of Drosophilamelanogaster appear to lack about 7 percent of single crossovers, and about 2 percent of double crossovers, if they arose from chiasmas (neglecting triple crossovers). Flies with heterozygous attached X’s in Drosophila, should (on the Billing’s theory) give distal recessive homozygotes in a percentage equal to half the chart length minus one and a half times the percentage of double crossovers. This would be 17.5. In Belling's theory, the percentages of complementary and identical non-crossovers, of crossovers plus non-crossovers, and of complementary crossovers, in attached X’s, have been calculated from the chromosome chart. It is possible to explain reversed crossing over, heterologous interchange, terminal translocation, inversion, deletion, and deficiency, by the overlapping of two chromonemas when their chromomeres are dividing. The result is equivalent to the formation of a chiasma between synapsed homologues; but is less regular, so that genes may be lost at the junctions (174).

Bryan H.C. Matthews (GB) showed that there exist in the mammal two distinct nerve-muscle systems in the skeletal musculature. The large motor nerve fibers set up the familiar motor unit twitch responses and the small motor nerve fibers increase the sensory discharges from muscle spindles, which consist of a number of so-called intrafusal muscle fibers (1801).

Ichiji Tasaki (JP) and K. Mizutani (JP) found that extrafusal muscle fibers in amphibia are innervated by two distinct motor systems. Motor neurons with large axons cause the familiar large fast twitches with single stimuli, known as the twitch system, while motor neurons with small axons require repetitive stimulation to cause slow and relatively weak contractions, known as the tonic system (2690).

Bernard Katz (GB), in his studies of the frog, observed that stimulation of large, low-threshold, motor axons not only caused extrafusal contraction but also a short burst of afferent impulses. The afferent firing persisted when extrafusal contraction was blocked by critical dosage with the muscle relaxant curare, thus showing that the large motor axons branched to innervate intrafusal muscle fibres. When muscle shortening was allowed, the tendency of extrafusal contraction to silence the spindle was offset by the intrafusal contraction. Katz discussed the significance of this clearly, with the proposal that when an extended muscle is contracted actively in life, the inevitable simultaneous intrafusal contraction would ensure that afferent activity continues, which would support the contraction against loading by means of the stretch reflex (1411).

Richard Benedikt Goldschmidt (DE-US) interbred various geographical races of the gypsy moth, Lymantria dispar. The moths that resulted from this cross showed that characters distinguishing local varieties are transmitted to the offspring and, therefore, can be explained in terms of Mendelian laws as being determined by genes. This was the first genetic explanation of geographic variety (1043).

Teikichi Fukushi (JP) was the first to provide experimental evidence of plant virus multiplication in insects. He was also the first to demonstrate transmission of a plant virus through the eggs of the vector (transovarial passage) (974-976).

Ralph S. Muckenfuss (US), Charles Armstrong (US), and Howard A. McCordock (US) proved that the etiological agent of St. Louis encephalitis is a virus. They successfully infected monkeys with the virus of St. Louis encephalitis by intracerebral inoculation with human brain tissue from a patient who had succumbed to the disease (1927).

F.M. Muller (NL) reported on the anaerobic use of organic sources of reducing power by the purple sulfur photosynthetic bacteria. Growth was accompanied by the production or utilization of CO2 depending on the ‘redox level’ of the organic substrate (1934).

Ernest Witebsky (DE-US) and Werner Henle (DE) discovered that bacteria indistinguishable morphologically and in culture could be subdivided by immunological tests (3041).

Robert E. Foster (US) and Carlton Earl Burnside (US) described a new disease found within broods of the honeybee, Apis mellifera Linn., which they named parafoulbrood (930). In 1935, they named and identified the etiological agent Bacillus para-alvei.

James Frederick Bonner (US) discovered that the most important growth constituent of the yeast extract is thiamine (vitamin B1) and subsequently White found that the effect of the yeast extract could be obtained by substituting the B-group—thiamine, pyridoxine and niacin—instead (250).

Roger-Jean Gautheret (FR) successfully cultured wound tissue or callus from the excised cambial tissue of Salix capraea and Populas alba. He used nutrient media solidified with agar but found that after 6 months the activity of the cultures ceased (1003). By including indoleacetic acid (IAA) and the vitamins B in his media Gautheret extended the culture period of the Salix callus to 18 months and was able to subculture. However after 18 months once again growth ceased.

H.J. Wilson (US), Herbert W. Israel (US), and Frederick Campion Steward (GB-US) developed methods to grow whole carrots (Daucus carotus) from single carrot cells rather than from the seed (3028).

Alexander Ivanovitch Petrunkevitch (RU-US) wrote, An Inquiry Into the Natural Classification of Spiders, Based on a Study of Their Internal Anatomy, which is the first comparative anatomy for any group of arthropods that can be used in classification (2086).

Johannes Friedrich Karl Holtfreter (DE-US)) performed experiments where gastrula tissue from young embryos was transplanted into ectoderm of older embryos. He found that the reacting tissue developed according to its surroundings. The conclusion is that the whole is controlling the events in its parts (1263, 1264, 1266).

Johannes Friedrich Karl Holtfreter (DE-US) performed exogastrulation studies wherein the dorsal mesoderm failed to make contact with the overlying ectoderm. In these instances, the ectoderm did not acquire a neural character, again suggesting that the inducing signal appeared to be transmitted vertically from the mesoderm to the ectoderm (1265).

Conrad Hal Waddington (GB), Noel Joseph Terence Montgomery Needham (GB), and Jean Louis Auguste Brachet (BE) hypothesized that the evocator substance was produced throughout the embryo, but it was just released or activated in one particular region (2850).

Aaron Bodansky (RU-US), Lois F. Hallman (US), and Kissel Bonoff (US) described the factors, which influence accuracy during the determination of serum phosphatase (238). Elevated levels of these enzymes can be a useful index of abnormal conditions in certain tissues.

Rudolpho Margaria (IT), Harold T. Edwards (US), and David Bruce Dill (US) defined the components of the oxygen debt and described what become known as the anaerobic threshold, i.e., the rate of appearance of lactic acid in the blood and its influence on ventilation during exercise (1767).

Karl Landsteiner (AT-US) and James van der Scheer (US), discovered that antibodies can be formed to and subsequently bind with exquisite specificity to completely synthetic compounds (1579, 1584).

Lionel Sharples Penrose (GB) was the first to show the significance of the mother’s age in Down’s syndrome. He determined that birth order, parity, and length of interval between pregnancies are not significant etiological factors (2068).

Lemuel W. Diggs (US), Chester Frederick Ahmann (US), and Juanita Bibb (US) demonstrated that there is a distinct difference between people with sickle-cell anemia and those who carry a slight sickling "trait" but have none of the other symptoms. They documented the diminished sickling of red blood cells from erythrocytes in newborns, and defined the ratio of patients with sickle cell anemia to carriers of sickle cell trait (692).

John Burdon Sanderson Haldane (GB-IN) suggested that the immune response of mice allowing them to reject tumors which arose in a different strain would be directed against normal cellular antigens unique to that strain rather than against tumor-specific antigens unique to the tumor (1127).

Louis Barkhouse Flexner (US) proved that cerebro-spinal fluid is produced by a secretory process in the choroid plexuses (915, 916).

Cicely D. Williams (GB) described a nutritional disease among the children of the Gold Coast of Africa, which the natives called Kwashiorkor, meaning the red or brown boy. The symptoms of the disease are: (1) edema of the hands and feet, (2) profound wasting, (3) dry, scaly skin with patches devoid of pigmentation, (4) hair which is dry, sparse, and often a dull reddish, muddy color, (5) diarrhea and irritability, (6) fatty degeneration of the liver at necropsy. The disease was common to children between one and four years of age who typically had been weaned following a long period of breast-feeding. The diet of these children was mostly cereal, maize, with no milk (3001, 3002).

Joseph Clarence Hinsey (US) and Joseph E. Markee (US) proposed that “pathways from the hypothalamus must activate the posterior lobe of the hypophysis which in turn may exert an influence on the anterior lobe by hormonal transmission" (1239).

Jesse D. Figgins (US) found large, heavy fluted stone points near Clovis, New Mexico. Mammoth bones in a deposit beneath a layer containing Folsom points and bison skeletons accompanied them. The robust points, now named Clovis, were recognized as even older than the Folsom points. Characteristic of both points is a flute, a flake struck off the base along the length of the point, presumably to facilitate hafting (896).

In 1964, C. Vance Haynes, Jr. (US) used radiocarbon dating to place the Clovis points at about 9,500-9,000 B.C.E., and none before 10,000 B.C.E. (1191).

Rene Neville (FR), in 1933, was the first to excavate fossil remains of Homo sapiens sapiens. The source was a cave site near Nazareth, Israel, on the southwest flank of Mount Qafzeh (1978). Subsequently more human fossil remains have been discovered at this site, all dated ca. 100,000 B.P.

1934

"No single feature of man's past equals in importance his attempt to understand the forces of Nature and himself. It is a safe prediction that the historian of the future will be concerned increasingly with the chronicle of the intellectual acquisitions of man, for this deeper story includes not merely improvement in material comforts but mental enlargement which transcends every other feature of human evolution." Herbert McLean Evans (850).

"Long ago I learned from my father to put old people to bed only for as short a time as was absolutely necessary, for they were like a foundered horse, if they got down it was difficult for them to get up, and their strength ebbed away very rapidly while in bed." Charles Horace Mayo (1805).

Harold Clayton Urey (US) was awarded the Nobel Prize in Chemistry for his proof that hydrogen gas contains a few atoms in which the nuclear proton is accompanied by a neutron. This so called “heavy hydrogen” was given the name deuterium.

George Hoyt Whipple (US), George Richards Minot (US) and William Parry Murphy (US) were awarded the Nobel Prize in Physiology or Medicine for their discoveries concerning liver therapy in cases of anemia.

Irène Joliot-Curie (FR), Hans von Halban (AT), Peter Preiswerk (CH) and Frédéric Joliot (FR) discovered that radioactivity could be induced artificially using alpha ray bombardment from radium. This methodology rapidly made available such valuable isotopes as 32P and 35S (1371-1373).

Marcus Laurence Oliphant (AU), Paul Harteck (GB), and Ernest Rutherford (NZ-GB) bombarded deuterium with the nuclei of deuterium atoms and produced tritium (hydrogen-3), the only radioactive form of hydrogen known. Tritium is much used in biochemical research (2010).

The first organic fungicide dithiocaramae was introduced. It proved valuable in foliar sprays for the control of a range of pathogenic fungi such as the scabs and rots of fruit and potato blight. ref

John Desmond Bernal (GB), and Dorothy Mary Crowfoot-Hodgkin (GB) were the first to take an x-ray diffraction photograph of a crystalline protein. It was of the enzyme pepsin (196).

Alfred Clarence Redfield (US) discovered that the atomic ratios between the chemical components of marine plankton, specifically nitrogen, phosphorus, and carbon are identical with their relative proportions in the open ocean. For every atom of phosphorus there are fifteen atoms of nitrogen and 105 atoms of carbon (carbonate and bicarbonate carbon are not considered organic) (2205).

Karl Meyer (US) and John W. Palmer (US) isolated hyaluronic acid in pure form from vitreous humor, and determined its correct composition (1856).

Robert Robinson (GB) hypothesized that cholesterol is formed by the cyclization of squalene, a polyisoprenoid hydrocarbon (2261). See, E.A. Rudolph, 1925.

A.P. Kiesel (RU) and Andrei Nikolaevitch Belozersky (RU) were the first to isolate thymine and then DNA (thymonucleic acid) from higher plants (176, 1438).

Andrei Nikolaevitch Belozersky (RU) and I.I. Dubrovskaya (RU) isolated DNA in the pure state for the first time (176).

Leopold Stefan Ruzicka (HR-CH), Moses Wolf Goldberg (EE), Jules Meyer (), Heinrich Brüngger (CH), and E. Eichenberger () synthesized the sex hormone androsterone from epidihydrocholesterol. This was not only the first synthesis of a sex hormone, but also the first complete structural elucidation of such a compound, and the first exact proof of the relationship between a sex hormone and a sterol (2333).

Hans Lineweaver (US) and Dean Burk (US) determined that if the reciprocal of the velocity of an enzyme catalyzed reaction is plotted against the reciprocal of the substrate concentration a straight line is obtained, and that this cuts the two axes at the reciprocal of V (velocity) and the reciprocal of Km respectively. This is commonly referred to as a Lineweaver-Burk plot (1681). Curiously enough this type of plot was first published in Kurt Guenter Stern’s German translation of John Burdon Sanderson Haldane’s book Enzymes (1932) where it was credited to Barnet Woolf (GB). Woolf likely failed to publish due to illness.

John R. Marrack (GB) proposed the lattice theory of antigen-antibody coupling with its fundamental requirement that antibody must have at least two antigen-combining sites (1775).

Russell Earl Marker (US) and John Krueger (US), in 1939, developed a method for synthesizing progesterone in large quantities from fats and oils of plants. They developed the process, initially for Parke Davis and Co., for degrading sapogenins to C21 steroids (1773). Marker, applied this process in 1941, to convert diosgenin from the wild Mexican yam into progesterone.

Vincent Brian Wigglesworth (GB) proved by experiment that during larval stages the corpus allatum (corpora allata) secretes a metamorphosis hormone, commonly called the juvenile hormone or neotenin, or youth substance. Under the influence of this hormone the larval characters are retained. When the larva is fully-grown, the corpus allatum (corpora allata) no longer secretes the hormone, the adult characters are developed, and metamorphosis occurs. His experimental animal was the large South American blood-sucking hemipteran Rhodnius prolixus.

In the 1940a paper he also argues that patterns derive from the diverse behavior of single cells — “the tiny fragment of cuticle laid down by a single cell may possess morphological characters controlled by the activity of that cell alone” (2991, 2994-2996). This physiological behavior has now been shown in almost all groups of insects.

Vincent Brian Wigglesworth (GB) found that the metamorphosis hormone is not genus specific and that egg formation in Rhodnius is dependent on the secretory function of the adult corpus allatum (corpora allata) (2992).

Jean-Jacques Bounhiol (FR) discovered that removal of the corpus allatum (corpora allata) results in precocious metamorphosis of the immature larval insect (261). By removing the corpus allatum (corpora allata) a conservative factor or status quo hormone is removed. Its function is to stabilize the larval tissues as larval tissues and the imaginal discs as imaginal discs. This status quo hormone became known as the juvenile hormone.

Vincent Brian Wigglesworth (GB) used implantation experiments to show that protocerebral neurosecretory cells are the source of the insect hormone that initiates the molting cycle (2993). This was the first experimental demonstration of an endocrine role for neural cells in any animal.

Note: During the period 1934-1936, the Kendall group, the Reichstein group, and the Pfiffner-Swingle-Wintersteiner group were all purifying steroid hormones from the adrenal cortex. They were designating them with letters of the alphabet which created confusion because A in one group was not necessarily A in another group. The Kendall group isolated and crystallized five would be hormones. As the structure of these compounds was worked out, it became possible to name them. In the Kendall series Compound A is 11-dehydrocorticosterone, Compound B is corticosterone, Compound E is 17-hydroxy-11-dehydrocorticosterone (cortisone), and Compound F is 17-hydroxy-corticosterone (cortisol or hydrocortisone). In 1949, Edward Calvin Kendall (US), and Phillip Showalter Hench (US) gave the name cortisone to17-hydroxy-11-dehydrocorticosterone (1429).

Lewis Hastings Sarett (US), working in the laboratory of Merck & Co., developed a method for synthesizing cortisone in quantities sufficient for clinical testing (2367).

Hans Hugo Bruno Selye (AT-CA) coined the group names glucocorticoids for the 11-oxy steroid hormones of the adrenal cortex and mineralocorticoids for the hormone(s) of the adrenal cortex affecting the metabolism of electrolytes and water. ref

Jakub (Jacob) Karol Parnas (PL), Pawel Ostern (PL), and Thaddeus Robert Rudolph Mann (PL-GB) resolved that, “… the resynthesis of phosphocreatine and adenosine triphosphate (ATP) is not linked to glycolysis as a whole, but to definite partial processes: and this leads further to the conclusion that this resynthesis does not involve a relationship that might be termed energetic coupling, but more probably involves a transfer of phosphate residues from molecule to molecule.” In this article they describe for the first time the presence of pyruvate kinase (phosphoenol transphorylase) and the fact that it catalyzes the magnesium- and potassium-dependent transphorylation between phosphoenolpyruvate and ADP (2041).

Otto Fritz Meyerhof (DE-US) and Karl Lohmann (DE) isolated the enzyme from muscle extracts that cleaves fructose-1, 6-diphosphate into two triose phosphates. They initially called it zymohexase but later Meyerhof, Lohmann, and Philipp Schuster (DE) changed it to fructose-biphosphatealdolase. They also recount their discovery of triose-phosphate isomerase (1874, 1878, 1879).

Karl Lohmann (DE) and Otto Fritz Meyerhof (DE-US) showed that the formation of pyruvic acid involves the enzyme catalyzed migration of the phosphoryl group from the 3-position to the 2-position of glyceric acid, followed by the dehydration of 2-phosphoglyceric acid to 2-phosphoenolpyruvic acid (PEPA) by the enzyme enolase (phosphopyruvate hydratase). This enzyme was found to be strongly inhibited by fluoride, thus explaining the effect of fluoride on alcoholic fermentation and glycolysis (1699).

Wilhelm Kiessling (DE) found that a ketotriose identical to synthetic dihydroxyacetone phosphate is a reaction product when hexosediphosphate is split into two trioses (1439).

Harland Goff Wood (US) and Chester Hamlin Werkman (US) were the first to isolate and identify pyruvic acid as an intermediate in the propionic acid fermentation (3053).

Karl Lohmann (DE) used dialyzed muscle extracts and found that the hydrolysis of creatine phosphate to creatine and phosphate is promoted by the addition of ATP, which is cleaved to adenylic acid (adenosine monophosphate) and two equivalents of inorganic phosphate. He concluded that the ATP acts as a coenzyme in the hydrolysis of creatine phosphate. He identified ATP as the coferment (coenzyme) of lactic acid formation in muscle and determined that it required the presence of the magnesium ion (1695).

Isaac McKinney Lewis (US) measured the frequency of lactose-negative tolactose-positive mutations in Escherichia coli mutabile and found it to be on the order of one mutation/one hundred thousand cells/cell generation (1652).

Phineas W. Whiting (US), working with Habrobracon, was the first to study what would later be called conditional lethal mutants (2975).

Norman Harold Horowitz (US) and Urs Leupold (CH) were the first to isolate temperature-sensitive mutants of bacteria. Such mutants are only able to grow at temperatures lower than that at which the wild-type is able to grow (1284).

Ernst Hadorn (CH) coined the term conditional lethal mutant to describe mutants of Drosophila which were either lethal, or allowed relatively normal development to occur, depending upon the growth conditions imposed by the experimenter (1123).

Henry Hallett Dale (GB) and Wilhelm Sigmund Feldberg (DE-GB) reasoned that the substance released by stimulated nerves which provokes the contraction of eserinized (eserine blocks acetylcholinesterase) leech muscle must be acetylcholine (590).

Ragnar Arthur Granit (FI-SE) and Per-Olof Therman (SE) established that details of the visual image are elaborated by the interplay of excitation and inhibition in the nervous center of the retina, i.e., that light can both excite and inhibit and that the two opposite processes are antagonistic. They did this by recording the mass discharge in the optic nerve together with the electroretinograph (1068, 1069).

Charles Armstrong (US), and Ralph Dougall Lillie (US) appear to be among the first to describe an infection caused by the virus of lymphocytic choriomeningitis (acute aseptic meningitis, idiopathic meningitis). It appeared as a contaminant in monkeys inoculated with the virus of St. Louis Encephalitis (70).

Claud D. Johnson (US) and Ernest William Goodpasture (US) filtered the mumps agent through Berkefeld V and N filters then with the filtrate produced the disease in monkeys. This was proof that mumps (epidemic parotitis) is caused by a virus (1364).

Karl Habel (US) succeeded in growing the mumps virus in the chick embryo. He also demonstrated a good correlation between the skin reactions to virus grown in the chick allantoic sac and in the monkey parotid gland. Because of the greater availability of egg-grown virus, the wider use of this reaction then became possible (1120).

Jeanette H. Levens (US) and John Franklin Enders (US) developed a hemagglutination test to titer the mumps virus (1641). They also showed that influenza A virus could be assayed by hemagglutination.

Thomas Huckle Weller (US), and John Franklin Enders (US) grew the mumps virus in cell culture consisting of fragments of chick amniotic membrane nourished with a balanced salt solution and ox serum ultrafiltrate. They succeeded, where others had failed, by incorporating the recently available penicillin into their cultures (2940).

Ivan Claude Jagger (US) and N. Chandler (US) were the first to describe the big vein disease of lettuce and reported that it was soil-borne and infectious (1350).

Carl Clarence Lindegren (US) found that in Neurospora all asci in a single perithecium arise from a single pair of nuclei associated at the initiation of the perithecium (1677).

Wendell H. Tisdale (US) and Ira Williams (US) working for the Du Pont Chemical Company discovered the dialkyldithiocarbamates as fungicides (2737). This group includes thiram, ferbam, maneb, zineb and mancozeb which are all surface acting agents.

Ladislaus Laszlo Marton (US), Stuart Mudd (US), and David Lackman (US) were among the first to publish electron photomicrographs of biological specimens in the United States (1791, 1792, 1929). In 1937 Marton published the first electron micrograph of bacteria.

Alice Catherine Evans (US), using the Clark phage which she renamed B563, was the first person to utilize a phage to classify bacterial strains, thus founding the analytical field of phage typing (848).

Roy T. Fisk (US) developed the method of typing staphylococci by using bacteriophages (908).

Sanford B. Hooker (US) and Edna M. Follensby (US) discovered that the erythrogenic toxin of scarlet fever is in reality two closely related toxins, which they called erythrogenic toxins A and B (1271).

Florence Barbara Seibert (US) and John T. Glenn (US) prepared a large batch of PPD that has served as the standard reference material (PPD-S) in the United States (2430).

Louis Alphonse Julianelle (US) and Charlotte W. Wieghard (US) introduced the first classification of the staphylococci based on differences in antigenic structure. They recognized two serological types of staphylococci based of specific carbohydrates obtained by chemical fractionation of the organisms. Type A strains were found to be pathogenic and capable of fermenting mannitol, while type B was comprised of strains which failed to ferment mannitol and had little, if any, pathogenicity (1380).

Chester W. Emmons (US) modernized the taxonomic scheme of Sabouraud and others and established the current classification of the dermatophytes on the basis of spore morphology and accessory organs (833).

James E. Knott (US) and Mikhail Khristoforovich Chailakhyan (RU) independently discovered that the flowering process is prompted not by a substance(s) in the bud but rather by a substance(s) produced in the leaves. Knott said, “Though the response of the plant may be localized in the bud, the leaves appear to function in some way to hasten the reproductive response to the appropriate photoperiod….Accordingly, the part played by the foliage of spinach in hastening the response to a photoperiod favorable to reproductive growth may be in the production of some substance, or stimulus, that is transported to the growing point.” Chailakhyan studied Saratov millet, Perilla nankinesis, Helianthus annuus and Helianthus tuberosus (sunflower) concluding, “the processes induced by the changes in the length of daylight and leading to the reproductive development of plants (flowering and fruiting) occur within the leaf tissues. The formative process occurring in the zones of growth (growing points) are secondary changes dependent upon the functional activity of the leaf.” Chailakhyan further demonstrated that the chemical promoter of flowering is not specific to a species but can stimulate a number of species. He named this hormone florigen, flower former (428-430, 1475).

Ferdinand Gustav Julius Sachs (DE), in 1880 and 1882, had guessed that leaves produce a promoter of flowering. He never demonstrated it experimentally.

William T. Heron (US), William M. Hales (US), and Dwight Joyce Ingle (US) reported that repetitive contraction of skeletal muscle requires the activity of a substance(s), which can be extracted from the adrenal cortex (1222). This knowledge was developed into a bioassy for adrenal hormones that facilitated the purification of cortisone.

Balduin Lucké (US) suggested a viral etiology for a renal adenocarcinoma he observed in the Northern Leopard Frog, Rana pipiens. This is the first postulation of a virus infection of an amphibian (1715, 1716).

Wallace Osgood Fenn (US), Doris M. Cobb (US), Albert H. Hegnauer (US), Burton Sanford Marsh (US), Jeanne F. Manery (US), Walter R. Bloor (US), Thomas R. Noonan (US), Lorraine F. Haege (US), Lorin J. Mullins (US), and Robert B. Dean (US) made the first determinations of potassium, sodium, magnesium and calcium in nerve. They showed that intracellular potassium is mobile and that muscle potassium shifts in response to various environmental factors. They found that during muscle contraction potassium is lost from muscle in exchange for sodium, and that the process is reversed in recovery. This was the first time that sodium was shown to penetrate muscle. This work laid the foundation for the Hodgkin-Huxley hypotheses concerning initiation and propagation of nerve and muscle impulses and the magnitude and polarity of electrical potential differences across cell membranes. Fenn said, “The explanation for a loss of potassium from a muscle during activity is a matter of fundamental theoretical importance. In terms of the theory which I have been using as a guide, it is interpreted as an increase in the permeability of the muscle membrane of sufficient extent to permit sodium which enters then displaces one molecule of potassium” (870). They showed that potassium escapes from muscle during contraction in situ and that a large part of this potassium appears in the liver. Potassium uptake was linked with carbohydrate metabolism, particularly with glycogen deposition, and tends to follow the Cori cycle. Radioactive potassium was ingested as part of the first study of the kinetics of potassium metabolism and the demonstration that it is taken up by erythrocytes. Nearly all muscle potassium was found to be exchangeable, supporting the notion that it is maintained by an active energetic process (636, 870-885, 1197, 1945, 1992, 1993).

Frederick W. Madison (US) and Theodore L. Squier (US) defined the etiology of primary granulocytopenia (agranulocytic angina). They suggested that the primary granulocytopenia following the use of such drugs amidopyrine with a barbiturate might be the result of an allergic or anaphylactoid drug reaction (1753).

John Silas Lundy (US) brought to a climax a long series of trials by many workers when he used the intravenous introduction of Pentothal (thiopental sodium, a barbiturate) to put a patient peacefully to sleep on June 18, 1934. Pentothal rapidly became the standard induction agent, being much more pleasant than inhaling the pungent ether. It was not until the 1990s that propofol, a more rapidly metabolized agent with fewer side effects, finally replaced Pentothal. Lundy (US) is best known for introducing intravenous anesthesia into clinical practice (1724).

Ralph Milton Waters (US) and Erwin R. Schmidt (US) published their paper on the physiologic and pharmacologic effects of cyclopropane on the human body (2915).

J. Roswell Gallagher (US) described an outbreak of bronchopneumonia in a group of 16 boys living at a preparatory school (a closed community). He especially stressed that these children did not have pneumococcal pneumonia but something different--something "atypical" (990).

Robert A. Reimann (US) described a group of eight patients with chest infection but atypical clinical presentations and no chest pain. He coined the term "atypical pneumonia" because the manifestations in these patients differed greatly from those in patients presenting with acute pneumococcal pneumonia. Reimann's initial impression was that this illness was caused by a filterable agent, most likely a virus, but to this date the cause of his patients' illnesses remains unknown (2215).

Clive M. McCay (US), Mary F. Crowell (US), and Leonard Amby Maynard (US) studied the effects of food restriction on the life span of rats. They concluded that if an animal ate what it should and little more its life span was increased (1813, 1814).

Ivar Asbjørn Følling (NO) described phenylketonuria (PKU) and called attention to its association with serious mental deficiency. He developed a test for demonstrating phenylpyruvic acid found in the urine of a person with PKU (923).

Walter Edward Dandy (US) outlined his theory of vascular compression as a cause of trigeminal neuralgia (TN), and pointed to the main problem with that theory; namely, that vascular contact occasionally occurs without the production of pain and may be absent when neuralgia is present (607).

Peter J. Hamlyn (GB) and Thomas T. King (GB) confirmed that vascular compression of the fifth cranial nerve is an anatomical abnormality specific to TN (1139).

Alexandra Adler (AT-US) suggested that the thalamic arcuate nucleus of the brain is associated with taste (10).

Harry Dickson Patton (US) found evidence that the most important part of the taste area lay buried in the operculum, just below the facial regions (2047).

Michael Ellis DeBakey (US), four years after entering medical school, designed the first roller pump, which remains the basis for all cardiac by-pass surgery performed today (637).

Ralph A. Colp (US) was the first to describe a granulomatous inflammation of the terminal ileum and cecum called ileo-colitis (513).

Arthur Evans (GB) was the first to successfully operate on the thoracic region of the esophagus for cancer. He reported a 23-year cure of cancer of the cervical esophagus by radical excision of the cervical esophagus and larynx (849).

Philippe l'Héritier (FR) and Georges Teissier (FR) devised the population cage method for the experimental study of natural selection. They showed, among other things, that unfavorable mutations (such as bar) could be maintained in a population of Drosophila in a stable balanced polymorphism in spite of the deleterious effects of the mutation on the flies that carried it (1551-1553).

G. Edward Lewis (US) found the first Ramapithecus (Ramapithecus brevirostris), the earliest known hominid fossil, in deposits in the Siwalik Hills of Northern India (1649).

William Beebe (US) and Otis Barton (US) developed the deep diving bathysphere. This round steel submersible was used on August 5, 1934 for a drop to 3,028 feet into the ocean off Nonsuch Island (160, 566). Beebe is commemorated by Protopelagonemertes beebei Coe, 1936, Metapenaeopsis beebei Burkenroad, and Aeginura beebei Bigelow, 1940.

Auguste Piccard (CH-BE) developed this type of equipment into what he referred to as a bathyscaphe, i.e., a more maneuverable submarine balloon, but looking somewhat like a conventional submarine. In 1954 his second bathyscaph the Trieste descended 10,330 feet into the Mediterranean and in 1960 his third vessel Trieste II was lowered to 35,800 feet (10,900 m) when it touched bottom in the Marianas Trench.

Rudolf Schoenheimer (DE-US) and David Rittenberg (US) introduced the use of deuterium as an isotopic tracer into biochemical research in animals (2402). This methodology marked a milestone in biochemistry because for the first time an isotope was systematically introduced into an organic compound so that a defined reaction or pathway could be studied. See, Georg Charles de Hevesy, 1923.

Wolfgang Schott (DE), inspecting findings of the German Meteor oceanographic expedition of 1925-27, realized that the species whose shells were found in the muck of the seabed depended sensitively on the temperature of the water where the creatures had lived. The mix of foraminifera species could serve as a thermometer of past climates (2419).

Harold Clayton Urey (US), Samuel Epstein (US), Heinz A. Lowenstam (US), and Charles R. McKinney (US) were able to prepare a history of changing ocean temperatures over long geologic periods. This work was based on the knowledge that heavy isotopes of oxygen react more slowly than normal atoms. Thus the proportion of oxygen isotopes in a seashell depends upon the temperature of the ocean at the time the shell was formed (2764, 2768, 2769).

David Rockwell Goddard (US) and Leonor Michaelis (DE- US) found that reducing agents such as thioglycolic acid could break the disulfide linkages in keratin (hair, wool, feathers). They did not patent this discovery (1036). Thioglycolic acid and other thiol compounds became the basic ingredients of the permanent wave solutions used in the cosmetic industry.

Harry Bender (US) discovered that technical benzene hexachloride (BHC) is a potent insecticide. He added benzene to chlorine in a Dewar flask in the open air and noticed that part of the product which spilled on the ground “attracted and killed flies and bees” (178). See Michael Faraday, 1825 and Van der Linden, 1912.

Eric John Underwood (AU), John Francis Filmer (AU), and Hedley Ralph Marston (AU) showed that cobalt is a necessary element in the diet of animals (1782, 2761).

Ernst Klenk (DE) characterized a new type of acidic glycolipid—naming it substance X—from the brains of patients suffering from amaurotic familial idiocy (1458).

Ernst Klenk (DE) coined the term ganglioside to name substance X that he characterized in 1935 (1460).

Charles Robert Harington (GB) and Thomas Hobson Mead (GB) were the first to synthesize glutathione, a small naturally occurring polypeptide (1160).

Richard H. McCoy (US), Curtis E. Meyer (US), and William Cumming Rose (US) isolated the amino acid threonine from hydrolysates of fibrin and demonstrated that it is one of the essential amino acids in rats (1822, 1854).

Herbert E. Carter (US) synthesized all isomers of threonine and found that the L-isomer is the essential form in rats (404).

Charles Robert Harington (GB) reported that enlargement of the thyroid gland in hyperthyroidism was found to be associated with heart dysfunction, exophthalmos, and increased metabolic rate (1159).

Ya-Pin Lee (US), Akira E. Takemori (US), Henry Arnold Lardy (US), Ching-Yuan Su (US), Nancy Kneer (US), and Susan Wielgus (US) found that thyroid hormone and also dehydroepiandrosterone induced the synthesis of mitochondrial glycerol-3-phosphate dehydrogenase to as much as 20 times the normal concentration and formed part of the thermogenic system (1591, 1596, 1617, 1618).

Harold King (GB) purified and determined the structure of d-tubocurarine, one of the many alkaloids present in curare preparations (1449, 1450).

Kurt Guenter Stern (GB-US) using optical methods (a spectrophotometer) made the first direct observation of an enzyme-substrate complex (2635).

Béla Tankó (HU) and Robert Robison (GB) announced the discovery of phosphohexose kinase (2688).

Karl Zeile (DE) and Axel Hugo Theodor Theorell (SE) performed work, which led to the complete purification of cytochrome c and its characterization as a protein unit of molecular weight 13,000 with a porphyrin unit covalently linked to the protein by way of two cysteine residues (2710, 3097).

Otto Heinrich Warburg (DE), Walter Christian (DE), Alfred Griese (DE), Frank Dickens (GB), Gertrude E. Glock (GB), Bernard Leonard Horecker (US), Pauline Z. Smyrniotis (US), Jarvis Edwin Seegmiller (US), Paul A. Marks (US), Howard H. Hiatt (US), Hans Klenow (US), Efraim Racker (PL-AT-US), and Dan Couri (US) extensively studied and purified all of the enzymes found in the type of glycolysis called the phosphogluconate pathway, also known as the pentose phosphate pathway or hexose monophosphate shunt. This is a multifunctional pathway specialized to carry out four main functions: (1) generate reducing power in the form of NADPH, needed for the synthesis of fatty acids and steroids from acetyl-CoA, (2) to convert hexoses to pentoses, particularly D-ribose 5-phosphate, required for the synthesis of nucleic acids, (3) the oxidative degradation of pentoses by converting them into hexoses, which can then enter the glycolytic sequence, and (4) it is modified so as to participate in the formation of glucose from CO2 in the dark reactions of photosynthesis (559, 686-688, 1275, 1277-1280, 2902, 2908). Horecker (US) coined the phrase hexose monophosphate shunt in his 1951b paper mentioned above.

Hermann James Almquist (US) and E.L. Robert Stockstad (US) demonstrated that fecal microorganisms are capable of synthesizing vitamin K. They purified the vitamin under a high vacuum (41-45).

Phoebus Aaron Theodor Levene (RU-US) and Robert Stuart Tipson (US) determined that “…in desoxy-ribose nucleic acid the positions of the phosphoric acid radicals are carbon atoms (3) and (5) of the desoxyribose” (1640).

Otto Fritz Meyerhof (DE-US) and Wilhelm Kiessling (DE) found that muscle extract contains an isomerase, which catalyzes the conversion of synthetic D-3-phosphoglyceraldehyde to dihydroxyacetone phosphate (1872).

Otto Fritz Meyerhof (DE-US) and Wilhelm Kiessling (DE) showed that in glycolysis it is the oxidation of the aldehyde to the acid that balances the reduction of acetylaldehyde to ethanol (in alcoholic fermentation) or of pyruvic acid to lactic acid (in glycolysis), and that phosphoglycerol is not a necessary participant in the dismutation as Embden had proposed. They also demonstrated that in iodoacetate poisoned muscle extracts, the phosphoryl group of 2-phosphoenolpyruvic acid is transferred to glucose by way of ATP to yield hexose phosphates and pyruvic acid (1871).

Jakub (Jacob) Karol Parnas (PL) and Tadeusz Baranowski; Tadeush Baranowski (PL) found that in muscle extracts glycogen and inorganic phosphate can react to form hexose monophosphates if the oxidation-reduction process is blocked using iodoacetic acid and no ATP is being generated (2040). This was of importance because it established beyond doubt the participation of inorganic phosphate in the splitting of glycogen and the discovery of phosphorylase activity in muscles.

Hutton D. Slade (US), Harland Goff Wood (US), Alfred Otto Carl Nier (US), Allen Hemingway (US), and Chester Hamlin Werkman (US) reported that fixation of carbon dioxide by C3 and C1 addition is apparently a very general reaction among the heterotrophic bacteria (2520). At this time, it was dogma that carbon dioxide is an inert end product of the metabolism of all living forms except the specially adapted chemosynthetic and photosynthetic autotrophs.

Henry Arnold Lardy (US) and Julius Adler (US) found that propionate could be metabolized by carbon dioxide addition to ultimately yield succinate (1592).

Hans Adolf Krebs (DE-GB) found that the kidney contains separate oxidative deaminases for D- and L-amino acids and that both kidney and brain tissue will convert ammonium glutamate to glutamine and hydrolyze it back as well (1515, 1516).

Henry Borsook (US) and Geoffrey Keighley (US) concluded from nutritional studies that there is a continuing metabolism of protein, and that tissue proteins are constantly being synthesized from amino acids (257).

Charles Herbert Best (US-CA) and M. Elinor Huntsman (CA) reported that choline is a lipotropic agent that prevents deposition of fat in the liver (202).

Kenneth Bryan Raper (US) identified the slime mold, Dictyostelium discoideum, then with Theo M. Konijn (US) laid the groundwork for the later use of this organism as a model system for the study of intercellular communication (1488, 2194).

Hugh A. Davson (GB) and James Frederic Danielli (GB) proposed a protein-lipid sandwich model for the structure of cell membranes. This Davson-Danielli model proposed the idea of two layers of phospholipids sandwiched in between two outer layers of protein. The phospholipids were oriented with their hydrophilic ends at the two surfaces and their hydrophobic tails towards the interior of the membrane. This structure explained the stability of plasma membranes because of the strong hydrophilic and hydrophobic interactions. It also accounted for the fact that lipid-soluble substances could pass through a plasma membrane easily. They proposed that this membrane was approximately eight nanometers thick, and had small pores in the protein coat to allow the passage of certain molecules and ions (611, 618).

John Burdon Sanderson Haldane (GB-IN) was the first to estimate the spontaneous mutation rate of a human gene (1128).

Sterling Howard Emerson (US) and George Wells Beadle (US), using the attached-X chromosome in Drosophila melanogaster, were able to show that each crossover between chromosomes at the first division of meiosis could, with equal likelihood, involve either one of the two chromatids into which each chromosome is divided (142, 147, 831).

Royal Alexander Brink (CA-US) and Delmer C. Cooper (US) offered proof that crossing over involves an exchange of segments between homologous chromosomes in Zea mays (302).

George Wells Beadle (US) and Boris Ephrussi (RU-FR) implanted embryonic eye tissue from larvae of vermilion and cinnabar mutants into larvae of normal Drosophila flies and observed that, upon metamorphosis of these larvae into mature flies, the implanted eye tissue developed into supernumerary eyes with normal eye color. It could be concluded, therefore, that the body tissues of the normal flies supply some substance that the vermilion and cinnabar mutant eye tissues are unable to synthesize, but one they can convert into the brown eye pigment. Beadle and Ephrussi then implanted the same embryonic mutant tissues into the larvae of vermilion and cinnabar mutant flies and observed that vermilion eye tissue implanted into cinnabar host larvae developed the normal eye color, whereas cinnabar eye tissue implanted into vermilion host larvae developed the mutant cinnabar eye color. Beadle and Ephrussi inferred from these observations that the synthesis of the brown eye pigment arises by the metabolic chain: Precursor to substance I to substance II tobrown pigment.

The vermilion mutant would thus carry a block in the reaction that converts the precursor to substance I, whereas the cinnabar mutant would carry a block in the reaction that converts substance I to substance II. Thus in the wild-type host larva, both of the mutant eye-tissue transplants are provided with substance II, which they can convert to the brown pigment. The vermilion mutant eye-tissue transplant in the cinnabar host larva is provided with substance I, which it can convert to substance II and to brown pigment. But the cinnabar mutant eye-tissue transplant in the vermilion host larva is not provided there with the substance II, which it lacks, and hence fails to form the brown pigment. Within a few years biochemical studies showed that the precursor is the amino acid tryptophan and that substances I and II are formylkynurenin and hydroxykynurenin, respectively. The genetically controlled metabolic eye color sequence could thus be written as: tryptophane toformylkynurenin (substance I) tohydroxykynurenin (substance II) tobrown pigment.

The stage was now set for formulating more clearly the physiological role of genes. The normal, wild-type allele of the vermilion gene of Drosophilacould be envisaged as presiding over the formation of an enzyme that catalyzes the conversion of tryptophan to formylkynurenin. The mutant allele, by contrast, has lost the capacity to form that enzyme. Hence the tissues of a homozygous mutant fly carrying the vermilion mutant gene on both of its homologous chromosomes lack the enzyme, and the metabolism of such flies is blocked at the reaction step normally catalyzed by that enzyme. The tissues of a heterozygous fly, carrying one mutant and one wild-type allele of the vermilion gene, would contain the enzyme, however, and hence are capable of forming formylkynurenin. Similarly, the mutant gene of the cinnabar gene has lost the capacity to form the enzyme that catalyzes the conversion of formylkynurenin to hydroxykynurenin, the enzyme that is normally formed under the direction of the wild-type allele. From this viewpoint, the recessive character of both the vermilion and cinnabar mutations is accounted for by the absence of an enzymatic function that the dominant, wild-type allele can supply (148, 149, 843, 844).

George William Beadle (US) found that fat bodies of all eye color mutants studied, except those from vermilion larvae, are shown to produce v+ substance following transplantation to appropriate test animals. Malpighian tubes of wild type larvae release both v+and cn+substances following transplantation. Both substances can be extracted from the larval tubes with hot Ringer’s solution. It was possible to demonstrate the presence of v+substance in the blood of wild type larvae during some part or all of a 24-hour interval just prior to puparium formation (143).

Alfred Kuhn (DE), Adolf Friedrich Johann Butenandt (DE), Wolfhard Weidel (DE), and Erich Becker (DE) did very similar work in Ephestia, studying the biochemical genetics of eye-pigment synthesis (374, 1534). These works represent the first step toward the one gene, one enzyme, hypothesis.

Nikolai Wladimirovich Timoféeff-Ressovsky (RU), Karl Günter Zimmer (DE), and Max Ludwig Henning Delbrück (DE-US) formulated a target theory of gene mutation, which says that a mutation can be induced if a single electron is detached by high energy radiation (2728).

Calvin Blackman Bridges (US) showed that inDrosophila salivary gland chromosomes certain sequences recur in different regions and that these tend to be found paired in the form of synapsis of somatic chromosomes. He referred to these regions as repeats and assumed that they had arisen as duplications of the same segment (tandem repeats) (293, 294).

Nagaharu U; Woo Jang-Choo (Korean-JP) discovered the evolutionary scheme of three allopolyploid species of Brassica based on three diploid species of genome donors. He used both the chromosome numbers and synthetic hybrids to prove the model and showed that rutabaga could be synthesized by crossing turnip and cabbage (624, 1958, 2342).

Erwin Bünning (DE) proved the genetic origin of biological rhythms. He found that circadian rhythms persisted in the bean plant Phaseolus and the fruit fly Drosophila, even though generation after generation had been raised in environments completely lacking cues to the passage of time (339, 340).

J. Arthur Ramsay (GB) investigated water loss from the American cockroach, Periplaneta americana. He found that very high wind speeds significantly increased rates of water loss, attributing this result to eddies set up within the tracheal system, increasing water evaporation from inside the tracheal system itself. Ramsay provided evidence for what was later termed the critical or transition temperature for water loss. Water-loss rates increase rapidly above this temperature. Ramsay then performed the first biophysical measurements on surface (cuticle) waxes, finding that the surface tension of wax-coated droplets decreased dramatically at about 30°C, right where water loss began to increase. He concluded that melting of these same lipids on the cockroaches' cuticle was responsible for increased transpiration (2164).

In a striking example of convergent evolution, most terrestrial organisms have similar lipid waterproofing layers (1121).

Wendell Meredith Stanley (US) reported the crystallization of pure tobacco mosaic virus to the world. This gave rise to the controversy of whether a virus is alive or dead. Most microbiologists today consider that they are not alive, because they are acellular (2606-2609).

J.P. Cleary (US), Paul J. Beard (US), and Charles E. Clifton (US) concluded that the population of a bacterium in continuous culture will not exceed a specific maximum cell number even when the effects of inhibitory substances are reduced to a low level because the major population limiting factor appears to be the amount of energy and building material available per cell per unit time (480).

St. Louis encephalitis was first recognized as a unique clinical entity in association with a large outbreak of the disease at St. Louis, MO in the summer of 1933 (515).

Leslie T. Webster (US), Anna D. Clow (US), and Johannes H. Bauer (US) found that the Anopheles quadrimaculatus (mosquito) will harbor the virus of St. Louis encephalitis for 21-42 days following a blood meal from an infected animal (2928).

Kenneth M. Smith (GB) and John G. Bald (GB) were the first to describe tobacco necrosis disease as being caused by a virus (2537).

William Trager (US) performed the first successful infection of insect tissue in vitro by an insect virus (grasserie). He inoculated primary cultures of ovarian tissue from Bombyx mori with dilutions of hemolymph from diseased larvae (2746).

Meredith Hoskins (US) reported that when rhesus monkeys (Macacus rhesus) were inoculated simultaneously with neurotropic and viscerotropic strains of yellow fever virus the neurotropic strain appeared to have a very definite protective effect by reducing the virulence of the viscerotropic strain. This is referred to as the interference phenomenon and was first demonstrated in animals by Hoskins (1290).

Leonell C. Strong (US) established the C3H inbred strain of mice for the study of spontaneous carcinoma of the mammary gland (2658).

Emmy Klieneberger (GB) discovered L form bacteria when she found them growing in association with Streptobacillus moniliformis. Originally she thought they represented a unique organism but other workers subsequently showed them to be a bacterial variant of organisms such as Streptobacillus moniliformis (1461). These organisms lack cell walls but are not mycoplasmas.

Gerhard J. Domagk (DE) discovered that a red dye compound, Prontosil rubrum (4-sulfonamido-2, 4-diamino-azobenzene hydrochloride) is very low in toxicity to animals but very active against streptococcal infections in animals (715).

Jacques Gustave Marie Tréfouël (FR), Thérèse Tréfouël, née Boyer (FR), Filomena Nitti (IT-FR), and David Bovet (CH-FR), working at the Pasteur Institute, discovered that the antibacterial action of the drug prontosil is due to it being converted to sulfanilamide within the animal body (2753).

Albert Spear Hitchcock (US) and Mary Agnes Chase (US) prepared the Manual of Grasses of the United States (1935). Its usefulness continues through today in the form of a 2nd edition in 1950 (1244, 1245).

An easy way to store blood plasma was discovered. It was first frozen, and then dried into flakes in a vacuum. Packed in tiny ampullae, the plasma was shipped with a pint of sterile water and tubing. ref

Dempsie B. Morrison (US), Alan Hisey (US), and Erich Peters (US) established that the combination of oxygen with hemoglobins takes place according to the ratio, Fe/O2, one gram-atom of pigmentary iron per gram-molecule of oxygen fixed (1922).

William Frederick Windle (US) and Marvin F. Austin (US) described the routes of the earliest axons in the central nervous system of the chick embryo, assessed at several stages between the second and sixth days of incubation. They focused on the descending, or reticulospinal, axons arising from hindbrain nuclei (3030).

William L.R. Cruce (US), Sherry L. Stuesse (US), and R. Glenn Northcutt (US) used retrogradely transported axonal tracers (horseradish peroxidase and Fluoro-Gold) to identify groups of brainstem neurons that projected to the spinal cord, in two cartilaginous fishes, the Thornback Guitarfish, and the Horn Shark. They identified numerous distinct reticular nuclei in these elasmobranchs, consistent with a complex organization similar to the reticular formation in other vertebrates (573).

John G. New (US), Bethany D. Snyder (US), and Katherine L. Woodson (US) traced axons descending to the spinal cord in the Channel Catfish, and found that the majority of neurons projecting to the spinal cord are located in the reticular formation of the hindbrain. Both ascending and descending reticular formation projections are of great clinical importance in humans, as they can be damaged or destroyed by strokes, spinal cord injuries, and astrocytomas (1979).

Eli Kennerly Marshall, Jr. (US) and Morris Rosenfeld (US) observed that in respiratory depression anoxia provides a major ventilatory drive mediated through the sino-aortic mechanism. Their observation recognized that often when the mammal is threatened with anoxemia, “it may adapt itself … to a primitive type of respiratory control (the sino-aortic rather than central) which is normal for lower vertebrates” (1778, 2298). See, Corneille and Jean Francois Heymans, 1927.

Note: It is a prime rule in accident rooms not to give oxygen to patients depressed with morphine, barbiturates, or allied drugs.

Carlyle F. Jacobsen (US) first discovered that damage to the primate prefrontal cortex (PF) appeared to cause a short-term memory deficit (1348, 1349).

Shintaro Funahashi (US), Charles J. Bruce (US), and Patricia S. Goldman-Rakic (US) found evidence to strengthen the evidence that the dorsolateral prefrontal cortex of the monkey participates in the process of working or transient memory and further indicate that this area of the cortex contains a complete “memory” map of visual space (979).

Armand James Quick (US), Margaret Stanley-Brown (US), and Frederic W. Bancroft (US) developed the one-stage prothrombin-time technique using rabbit brain extract. This test detects the amount of prothrombin present in blood plasma and determines prothrombin-clotting time (2149, 2150). The technique was based on the assumption that, given enough tissue, calcium, and fibrinogen, there is only one factor limiting the time course of clotting: prothrombin. It is now recognized that this result is limited by deficiencies of factors additional to prothrombin, but this does not diminish the importance of this technique in the control of coumarin therapy. See, Whipple, 1913.

The one-stage prothrombin-time made possible the immediate differentiation between the coagulation defect in hemophilia and that in obstructive jaundice.

Emory D. Warner (US), Kenneth M. Brinkhous (US), and Harry P. Smith (US) developed a method of measuring prothrombin, which became known as the two-stage technique (2913).

Hugh Leslie Marriott (GB) and Alan Kekwick (GB) introduced the continuous drip blood transfusion method, in which blood flows from a flask (1776). This was made possible by Luis Agote’s discovery in 1914. Earlier transfusions were directly from donor to recipient.

Claude Schaeffer Beck (US) presented his technique for development of a blood supply to the heart by operation. It prescribed grafting a flap of the pectoralis muscle over the exposed epicardium to provide a new blood supply (156).

Frank Mason Sones, Jr. (US) accidently performed the first selective coronary angiography when he accidently injected dye into the right coronary artery instead of into the cardiac valve as intended. Instead of fibrillating, the man's heart went into asystole, and Sones shouted at the patient to cough, which successfully restarted the heart beating (721, 1884).

W. Dudley Johnson (US), Robert J. Flemma (US), Derward Lepley, Jr. (US), and Edwin H. Ellison (US) introduced modern coronary by-pass surgery with their method of myocardial revascularization. Veins are usually inserted into an area of normal artery; however, if a second area of atherosclerosis occurs (commonly in the mid-anterior descending artery), the arteriotomy extends across the plaque into normal artery on each end. The vein is sutured as a patch graft always extending the anastomosis to normal artery proximally and distally. With progressive atherosclerosis this maneuver preserves bidirectional flow (1370).

H. Edward Garrett (US), Edward W. Dennis (US), and Michael Ellis DeBakey (US) performed an autogenous saphenous vein by-pass from the ascending aorta to the anterior descending coronary artery. The patient was a 42-year-old man who had extensive occlusive disease of the coronary artery and angina pectoris (998). This team first performed the operation in 1964.

Allen Oldfather Whipple (US), William Barclay Parsons (US), and Clifton R. Mullins (US) introduced a two-stage radical pancreaticoduodenectomy to treat carcinoma of the ampulla of Vater (2961). Twenty-eight months was the longest survival time course of the three cases reported. This was not the first time such an operation was performed.

Allen Oldfather Whipple (US) described the first reported case of a one-stage pancreaticoduodenectomy for a carcinoma of the head of the pancreas (2960).

Arnold Rice Rich (US) found carcinoma of the prostate in 14% of all autopsies and in 28% of those aged over 70 years (2226).

Burrhus Frederic Skinner (US), a leading behaviorist and proponent of operant conditioning, invented the Skinner box for facilitating experimental observations. His main scientific works include The Behavior of Organisms (1938), and Verbal Behavior (1957). He founded behaviorism (2513-2516).

John Ridley Stroop (US) was the first to think of combining a word with object/property dimensions, creating the now famous situation of response conflict (2659). An example of this phenomenon is that when asked to name the color of ink in which an incompatible color word is printed (e.g., to say "red" aloud in response to the stimulus word GREEN printed in red ink), people take longer than to name the same ink color in a suitable control condition (e.g., to say "red" to the stimulus XXXXX printed in red ink). This has been called the Stroop effect.

Arthur George Tansley (GB) coined and defined the term ecosystem. "The weakness of Clements is. . . that vegetation is an organism and therefore must obey the laws of development of what we commonly know as organisms. . . . But the more fundamental conception is, as it seems to me, the whole system (in the sense of physics) including not only the organism-complex, but also the whole complex of physical factors forming what we call the environment of the biome…Though the organism may claim our primary interest, when we are trying to think fundamentally we cannot separate them [organisms] from their special environment, with which they form one physical system" (2689).

Linus Carl Pauling (US) and Charles Dubois Coryell (US) demonstrated that in deoxyhemoglobin the bonds between iron and nitrogen are ionic and weak whereas in oxyhemoglobin they are covalent and stronger (2052).

Daniel Bovet (CH-FR-IT) and Anne Marie Staub (DE) synthesized the first histamine receptor antagonists (popularly referred to as the classical antihistamines but now called H1-receptor antagonists). These early studies of the antihistamines were qualitative, for example, the demonstration of their effectiveness in protecting against bronchospasm produced in guinea pigs by anaphylaxis or administration of histamine. Though qualitative, these studies yielded compounds that remain major ligands to define histamine receptors, e.g., mepyramine (pyrilamine) (266).

André Michael Lwoff (FR), Marguerite Lwoff (FR), Bert Cyril James Gabriel Knight (FR), and John Howard Mueller (FR) demonstrated that nicotinic acid is an essential growth factor for some bacteria (1470, 1732, 1733, 1930). This led to the use of bacterial growth as a quantitative assay of growth factors.

Klaas Tammo Wieringa (NL) discovered Clostridium aceticum, the first acetogenic bacterium found to grow with hydrogen as an energy source and carbon dioxide as a carbon source (2982, 2983).

Carl Ferdinand Cori (CZ-US) and Gerty Theresa Cori, née Radnitz (CZ -US) discovered that glucose-1-phosphate is formed naturally in muscle. This was evidence for the presence of glycogen phosphorylase (544). They presented evidence for phosphoglucomutase, the enzyme which converts glucose-1-phosphate to glucose-6-phosphate.

Chester Hamlin Werkman (US), E.A. Zoellner (US), Henry Gilman (US), and Howard Reynolds (US) were the first to isolate phosphoglyceric acid from bacteria (2948). Along with Robert William Stone (US) and Wilbur Paul Wiggert (US) they reported the formation of phosphoglyceric acid and related intermediary compounds in the dissimilation of glucose by a variety of heterotrophic bacteria (2645-2647, 2987).

Franz Knoop (DE) and Carl Martius (DE) established some of the intermediate stages of the oxidation of citric acid when they discovered the following sequence of reactions in liver tissue: citrate — cis-aconitate — isocitrate — oxalosuccinate — alpha-ketoglutarate.

The end-product of these sequences, alpha-oxoglutaric acid (alpha-ketoglutaric acid), was already known as an intermediate product because it is formed from the amino acid glutamate and had been shown to be oxidized to succinic acid (1474).

Carl Martius (DE) and Franz Knoop (DE) demonstrated that citric acid could be formed from pyruvic acid (1789). Carl Martius (DE) worked out the sequence citric-aconitic-isocitric-oxalosuccinic acid by the action of aconitase and isocitrate dehydrogenase (1788).

David Bodian (US) developed a new method for staining nerve fibers and nerve endings in mounted paraffin sections (240).

Peter A. Gorer (GB), using inbred strains of mice, discovered four blood group antigens. The growth and rejection of a tumor correlated with the expression of antigen II. Gorer formulated the concept of tissue transplantation as, “normal and neoplastic tissues contain iso-antigenic factors which are genetically determined. Iso-antigenic factors present in the grafted tissue and absent in the host are capable of eliciting a response which results in the destruction of the graft.” This represents the discovery of what came to be known as the H-2 genetic region in mice (1056, 1057).

Clara J. Lynch (US), Thomas P. Hughes (US), Leslie T. Webster (US), and Anna D. Clow (US) were the first to demonstrate that a host gene can control resistance to disease induced by an animal virus (1734, 2927). This resistance was directed against flaviviruses.

Cyril Norman Hugh Long (GB-US) and Francis D.W. Lukens (US) found that removing the adrenal gland and pituitary gland of a diabetic animal reduced the blood level of glucose and thus the severity of its diabetic state (1702). This would later be linked to adrenocorticotropic hormone (ACTH) of the anterior pituitary gland. ACTH stimulates the release of other hormones, which encourage the conversion of amino acids to glucose.

Torbjörn Oskar Caspersson (SE) demonstrated that the so-called euchromatin bands on chromosomes represent areas, which are very rich in nucleic acids (411).

Calvin Blackman Bridges (US), Eleanor Nichols Skoog (US), and Ju-chi Li (CN) chose the notopleural deficiency in Drosophila melanogaster to establish a close correspondence between the loci on the genetic maps, deduced from linkage studies, and the particular chromosome localities, deduced from study of the transverse bands which form a diversified series along the salivary chromosome (297).

George Henry Hepting (US) and Dorothy J. Blaisdell (US) described the mechanisms with which trees restrict the development of decay and discoloration in stems to “tissues extant at time of wounding.” This phenomenon is now known as compartmentalization (1218).

John Zachary Young (GB) discovered the giant nerve fibers of the squid, Loligo forbesi. This made possible many important experiments in neurophysiology (3090-3092).

Frederick Charles Bawden (GB), Norman Wingate Pirie (GB), Hubert S. Loring (US), Wendell Meredith Stanley (US), and Max Augustus Lauffer (US) demonstrated that all plant viruses tested up to this time were pure nucleoprotein. This was the first indication that nucleic acids, found in all cells, is found also in acellular "life" (138-141, 1709, 2611).

George P. Berry (US) and Helen M. Dedrick (US) reported the changing of rabbit fibroma virus (Shope) into infectious myxomatosis virus (Sanarelli). This Berry-Dedrick phenomenon has been referred to variously as transformation, recombination, multiplicity of reactivation, and non-genetic reactivation (199).

Frank Macfarlane Burnet (AU) and Dora Lush (AU) published a paper showing that bacteriophages can sport mutants whose plaques have a distinctly different appearance from those of the ordinary wild-type (354).

Jean Cuillé (FR) and Paul-Louis Chelle (FR) reported that scrapie can be serially transmitted to sheep and that it passes bacterial filters. They noted that signs of the disease did not appear until more than one year had elapsed from the time of exposure to the contagious material (574-576). Scrapie gets its name from the tendency of affected animals to rub against fence posts during the excitable phase of the disease.

Josef Gerstmann (AT-US), Ernst Sträussler (AT), and Ilya Mark Scheinker (AT) described a disease characterized by degeneration of the nervous system, starting usually in the fourth or fifth decade of life with slowly developing dysarthria and cerebellar ataxia and then dementia, accompanied by spinocerebellar and corticospinal tract degeneration, and absence of leg reflexes. Death follows 2 to 10 years after the onset of symptoms (1012). Today this is known as Gerstmann-Sträussler-Scheinker syndrome, one of the amyloid dependent subacute spongioform encephalopathies associated with prion infection. It behaves in an autosomal dominant pattern.

Bjorn Sigurdsson (IS), Páll Agnar Pálsson (IS), and Halldór Grímsson (IS) determined that both visna and maedi are slow virus infections of sheep (2500, 2502). Visna means wasting and is characterized by progressive neurologic impairment and inanition. Maedi means shortness of breath and is characterized as a chronic pneumonia. Sigurdsson developed the concept of slow infection and described it as: (a) a long but rather predictable incubation period of months to years, during which the infectious agent produces clinically unapparent but progressive pathologic damage; and (b) a protracted course, once clinical signs have appeared, generally ending in serious disease or death (2501).

Daniel Carleton Gajdusek (US) and Vincent Zigas (AU) were the first to describe kuru (shivering or trembling), a human spongiform encephalopathy discovered among the Fore people of New Guinea (989).

Wlliam J. Hadlow (US) pointed out the similarity in the neuropathology of scrapie in sheep with that of kuru in man. He arrived at this conclusion after observing brain sections of kuru victims prepared by Igor Klatzo (DE-US) (1122, 1455).

Herbert B. Parry (GB) suggested that scrapie, a spongiform encephalopathy of sheep, is an inherited but also transmissible disease (2042).

Tikvah Alper (GB) and John Stanley Griffith (GB) developed the hypothesis that some transmissible spongiform encephalopathies are caused by an infectious agent consisting solely of proteins (46, 1086).

David C. Bolton (US), Michael P. McKinley (US), and Stanley Ben Prusiner (US) argued that a protein, not a virus or any other known parasite, was the infectious agent responsible for scrapie (249). Prusiner named the infectious agents prions (proteinaceous infectious particle) (2136).

Karen Hsiao (US), Harry F. Baker (GB), Tim J. Crow (GB), Mark Poulter (GB), Frank Owen (GB), Joseph D. Terwilliger (US), David Westaway (US), Jurg Ott (US), and Stanley Ben Prusiner (US) showed that in Gerstmann-Straüssler-Scheinker (GSS) syndromeprion protein (PrP) codon 102 is linked to the putative gene for the syndrome in two pedigrees, providing the best evidence to date that this familial condition is inherited despite also being infectious, and that substitution of leucine for proline at prion protein (PrP) codon 102 may lead to the development of Gerstmann-Straüssler-Scheinker (GSS) syndrome (1303).

Dmitry Goldgaber (US), Lev G. Goldfarb (US), Paul Brown (US), David M. Asher (US), W. Ted Brown (US), Scott Lin (US), James W. Teener (US), Stephen M. Feinstone (US), Richard Rubenstein (US), Richard J. Kascsak (US), John W. Boellaard (DE) and Daniel Carlton Gajdusek (US) found a mutation in the prion protein (PrP) gene of two patients with Creutzfeldt-Jakob disease (CJD) from one family and a second mutation in the same gene in three patients with Gerstmann-Straüssler-Scheinker (GSS) from another family. The mutation in two related familial CJD patients changed glutamine in position 200 to lysine (1041).

Matti Haltia (FI), Jussi Kovanen (FI), Lev G. Goldfarb (US), Paul Brown (US), and Daniel Carleton Gajdusek (US) found a new G-to-A mutation in codon 178 of the PRNP gene (resulting in a substitution of asparagine for aspartic acid) in the DNA of eight family members with typical Creutzfeldt-Jakob disease (CJD) (1135).

Stanley Ben Prusiner (US) and Michael R. Scott (US) suggested that mutant prions have the capacity to reshape normal prions into versions of themselves by causing a change in their folding pattern (2141).

John Joseph Bittner (US), in mice, discovered a naturally transferable cancer agent that is transmitted through the milk of the mother to her offspring (211-213).

Henry Hallett Dale (GB), Wilhelm Sigmund Feldberg (DE-GB), and Marthe Louise Vogt (DE-GB) found that in the presence of eserine (it blocks the action of acetylcholinesterase), curare does not block acetylcholine release from the motor nerve terminals upon electrical stimulation but, of course, blocks the effect of acetylcholine on the muscle membrane (591).

Alister Clavering Hardy (GB) and Nora Ennis (GB) reported on the use of their plankton continuous recorder. Their aim was to develop a technique for estimating the numbers or weights of planktonic organisms beneath a unit area of sea surface or in a unit volume of water (1156).

Max Walker De Laubenfels (US) wrote an overview of all sponge genera. Presented as a monograph on the sponges of the Florida Keys, he revised almost casually all extant supraspecific taxa, erecting in the process several hundreds of new taxa. These paper taxa, i.e., erected by simply reading the descriptions in the previous literature, were mostly insufficiently established to be of use in sponge classification. Nevertheless, his book presented the first comprehensive overview of the genera and families of sponges, and it formed the basis for modern sponge classification (628). He is commemorated by Delaubenfelsia Dickinson, 1945; Endectyon delaubenfelsi Burton, 1930; Holoplocamia delaubenfelsi Little, 1963; Rhaphidophlus delaubenfelsi Lévi, 1963; and Xestospongia delaubenfelsi Riveros, 1951.

Karl von Frisch (AT) was the first to suggest that the tightly coupled otic gas bladder in the mormyrid fishes can transmit the sound pressure component of the acoustic signal into the inner ear to enhance overall hearing ability (2836, 2837).

Richard Edwin Shope (US) found evidence that the virus, which caused the 1918 influenza pandemic in humans, and the swine influenza virus are one and the same (2489).

M. Robert Irwin (US) and Leon J. Cole (US) established that antigens are inherited using the Ringdove, Streptopelia risoria, and the Pearlneck dove, Spilopelia chinensis, as their experimental material. The term immunogenetics was coined in this article (1344).

Ronald Aylmer Fisher (GB-AU) produced an article that represents a milestone in numerical taxonomy (906).

Thore Edvard Brandt (SE) described a zinc deficiency syndrome in infants, characterized by acral dermatitis, alopecia, diarrhea, steatorrhea, and anal pustular eruptions on the face and around body orifices (278). The syndrome is caused by the absence of the ligand essential for zing absorption, which is present in human but not cow milk. A similar disease picture may be seen in patients receiving artificial nutrition with low zinc content. Untreated, the disease is usually lethal.

Perrin Hamilton Long (US) and Eleanor A. Bliss (US) are credited with having introduced sulfonamides, which were the first effective antibacterial agents, to the United States. They used sulfanilamide in clinical applications at Johns Hopkins University in 1936 (1703, 1704, 1706).

Francis F. Schwentker (US), Sidney Gelman (US), Perrin Hamilton Long (US), and Eleanor A. Bliss (US) were the first to use antimicrobial therapy against meningococcal infections in demonstrating the efficacy of sulfonamides against meningococcus (1705, 2426).

Walter Thomas James Morgan (GB) and Stanley Miles Partridge (NZ-GB) were the first to describe the somatic antigen (endotoxin) of the Enterobacteriaceae as a toxin (1918-1920).

William Augustus Hinton (US) published the first major text on syphilis entitled Syphilis and Its Treatment (1241). Hinton developed the Hinton Test to detect syphilis in blood and spinal fluids, which reduced the number of false positive diagnoses of the disease. John A.V. Davies (US) improved the test to make it applicable to the cerebrospinal fluid. It then became known as the Davies-Hinton Test .

Arthur J. Patek, Jr. (US), Richard P. Stetson (US), and F.H. Laskey Taylor (US) found that patients with hemophilia are lacking afactor present in normal plasma. They called it anti-hemophilic factor(AHF) or anti-hemophilic globulin (AHG) (2044, 2045). This deficiencynow called hemophilia A (or factor VIII deficiency) is foundalmost exclusively in males and is one of the most common ofthe hereditary coagulation disorders

Yngve Zotterman (SE) isolated the single nerve units in the taste receptors of the tongue (682, 3113).

Harold P. Himsworth (GB) noted that there are two main types of diabetes, the insulin-depleted (type 1) and the insulin-resistant form (type 2). Insulin resistance is a term and concept of his coinage (1237).

Wilder Graves Penfield (US-CA) found that stimulation anywhere on the cerebral cortex could bring responses of one kind or another, but he found that only by stimulating the temporal lobes (the lower parts of the brain on each side) could he elicit meaningful, integrated responses such as memory, including sound, movement, and color. These memories were much more distinct than usual memory, and were often about things unremembered under ordinary circumstances. It seemed he had found a physical basis for memory, an engram. Penfield said, “there is hidden away in the brain, a record of the stream of consciousness” (2064-2067). In reality, however, the reported episodes of recall occurred in less than five percent of his patients, and these results have not been replicated by modern surgeons (1360).

Hans Hugo Bruno Selye (AT-HU-CA) proposed the concept of the stress syndrome after a twelve-year study of the physiological effects of stress on animals. He promoted the complex topic of stress as applied to every aspect of daily life or medicine (2437-2443).

Howard Bishop Lewis (US), Barker H. Brown (US), and Florence R. White (US) administered either cystine, cysteine hydrochloride, or dl-methionine, combined with a high or low protein diet to a cystinuric subject and measured the amount of extra cystine and sulfur excreted in the subject’s urine. They found that the administration of cystine did not affect cystine excretion, but it did induce a large increase in the sulfur content of the urine. Cysteine hydrochloride and dl-methionine, on the other hand, led to increases in the excreted amounts of both cystine and sulfate. Surprisingly, less extra cystine was excreted after methionine was administered to the subject when he consumed a high protein diet. These results led them to conclude, “the utilization of the precursor of the urinary cystine in cystinuria occurs more readily under conditions of a high level of protein metabolism." These experiments also confirmed an earlier hypothesis by Erwin Brand (US) who postulated that cysteine is a product of the catabolism of methionine and that the error in cystinuria is a failure of the proper utilization of cysteine and not of cystine. Thus, the extra cystine excreted after the feeding of methionine is derived directly from the degradation of methionine, with cysteine as an intermediary product (1651).

Paul Herbert Kimmelstiel (DE-US) and Clifford Wilson (GB) related that cases of kidney disease frequently, “show a striking hyaline thickening of the intercapillary connective tissue of the glomerulus. Evidence is presented which…suggests that arteriosclerosis and diabetes may play a part in its causation…. The characteristic clinical features are a previous history of diabetes, severe and widespread edema of the nephrotic type and gross albuminuria. Hypertension is frequently present.” This condition develops in about 20 to 25 percent of patients, in whom diabetes mellitus has been present for several years, usually beginning about 15 years after onset of diabetes and is often referred to as Kimmelstiel-Wilson syndrome (1446, 1447).

Robert Gesell (US), A. Kearney Atkinson (US), Richard C. Brown (US), Conway S. Magee (US), John W. Bricker (US), G. Stella (GB), Robert Franklin Pitts (US), Horace Winchell Magoun (US), and Stephen Walter Ranson (US) discovered that the respiratory center of the medulla is not a compact, sharply localized structure, but is scattered bilaterally in the gray matter of the ventral reticular formation of the medulla overlying the upper (cephalic) four-fifths of the inferior olive (1013-1016, 1755, 2107, 2109-2111, 2624, 2625). The location is practically the same in the dog and cat (1015, 2109, 2111).

Walter Jackson Freeman (US), with no qualifications for surgery, and James Winston Watts (US), in 1936, introduced a surgical technique for frontal lobe lobotomy into the U.S.A. The early 'technique' involved drilling burr-holes; later Freeman developed his famous/infamous transorbital approach, literally pushing an ice pick into the brain via the eye sockets (947, 948).

Harold Neuhof (US) and Arthur S.W. Touroff (US) detailed the principles of operative treatment for acute putrid abscess of the lung in the era prior to antibiotic availability (1977).

Carl Gottfried Hartman (US) finally described the 28-day menstrual cycle and calculated the most fertile period for women as 11 to 14 days after the first day of the menstrual flow (1174).

C.U. Ariens Kappers (US), G. Carl Huber (US), and Elizabeth Caroline Crosby (US) wrote their very important and influential book, The Comparative Anatomy of the Nervous System of Vertebrates, Including Man (1403).

Henry Norman Bethune (CA) realized that a frequent cause of death on the battlefield is medical shock brought on by loss of blood and that a casualty whose wounds do not appear life threatening could suddenly die. He conceived the idea of administering blood transfusions on the spot. He developed the world's first mobile medical unit. The unit contained dressings for 500 wounds, and enough supplies and medicine for 100 operations. Bethune organized a service to collect blood from donors and deliver it to the battlefront, thereby saving countless lives. His work during the Spanish Civil War in developing mobile medical units was a precursor to the later development of Mobile Army Surgical Hospital (MASH) units (1221, 2319). See, Dominique Jean Larrey, 1803.

Georges Girard (FR) and Jean-Marie Robic (FR) developed an anti-plague (Yersinia pestis) vaccine known as the EV strain (1033).

Remington Kellogg (US) wrote Review of the Archaeoceti, a landmark in cetology (1426).

Nikolaas Tinbergen (NL) devised many important and ingenious experiments to test aspects of animal behavior such as the releaser concept of Lorenz, sexual fighting in birds, social organization among vertebrates, begging response, and orientation mechanism (2729-2735).

The California Institute of Technology established its Marine Station at Corona del Mar, California.

1937

“Now my own suspicion is that the Universe is not only queerer than we suppose, but queerer than we CAN suppose.” John Burdon Sanderson Haldane (1130).

“What does it matter to Science if her passionate servants are rich or poor, happy or unhappy, healthy or ill? She knows that they have been created to seek and to discover, and that they will seek and find until their strength dries up at its source. It is not in a scientist's power to struggle against his vocation: even on his days of disgust or rebellion his steps lead him inevitably back to his laboratory apparatus.” Eve Curie Labouisse in her biography of Madame Curie (1555).

Clinton Joseph Davisson (US) and George Paget Thomson (GB) were awarded the Nobel Prize in Physics for their experimental discovery of the diffraction of electrons by crystals.

Walter Norman Haworth (GB) for his investigations on carbohydrates and vitamin C and Paul Karrer (RU-CH) for his investigations on carotenoids, flavins, and vitamins A and B2 were awarded the Nobel Prize in Chemistry.

Albert Imre Szent-Györgyi (HU-US) was awarded the Nobel Prize in Physiology or Medicine for his discoveries in connection with the biological combustion processes, with special reference to vitamin C and the catalysis of fumaric acid.

William S. Koffman (US) developed a rapid photoelectric method for the determination of glucose in blood and urine (1255).

Yasushige Ohmori (JP) reported a method for the determination of alkaline phosphatase in the blood (2007).

Tadeus Reichstein (PL-CH) discovered a steroid hormone from the adrenal cortex which he named substance M (cortisol) (2210).

Vilém Laufberger (CZ) isolated a crystallizable protein from horse spleen, which contained over 20 per cent by dry weight of iron. He named it ferritine (ferritin) and speculated that it served as a depot for iron in the body (1603).

Tomas Ganz (US) found that induction of hepcidin in inflammation and consequent iron sequestration augments innate immune defenses against invading pathogens. The resulting decrease in plasma iron levels eventually limits iron availability to erythropoiesis and contributes to the anemia associated with infection and inflammation (992).

Rudolf Schoenheimer (DE-US) and David Rittenberg (US) found that the degradation and synthesis of saturated fatty acids proceeds two carbon atoms at a time and saturated fatty acids can be converted to mono-unsaturated fatty acids and vice versa. When mice were fed fatty acids labeled with deuterium, most of the deuterium was recovered in the fat tissues rather than being immediately utilized, i.e., newly ingested fat is stored whereas older fat is used. When water labeled with deuterium was administered to mice, it was found that 50 percent of the hydrogen atoms of cholesterol derived from the hydrogen atoms of the water. Body fat is not static, as was previously thought, but rather in a dynamic turnover state even when adequate fat is supplied in the diet (2250, 2403).

Rudolf Schoenheimer (DE-US), David Rittenberg (US), Marvin Fox (US), Albert S. Keston (US), and Sarah Ratner (US) used heavy nitrogen (N15) labeled amino acids to trace the fate of amino nitrogen and found that there was rapid changing and shifting, even though the overall movement might be small. In their words, “It is scarcely possible to reconcile our findings with any theory which requires a distinction between these two types of nitrogen. It has been shown that nitrogenous groupings of tissue proteins are constantly involved in chemical reactions; peptide linkages open, the amino acids liberated mix with others of the same species of whatever source, diet, or tissue. This mixture of amino acid molecules, while in the free state, takes part in a variety of chemical reactions: some reenter directly into vacant positions left open by the rupture of peptide linkages; others transfer their nitrogen to deaminated molecules to form new amino acids. These in turn continuously enter the same chemical cycles, which render the source of the nitrogen indistinguishable. Some body constituents like glutamic acid and aspartic acid and some proteins like those of the liver, serum, and other organs are more actively involved than others in this general metabolic pool originating from interactions of dietary nitrogen with the relatively larger quantities of reactive tissue nitrogen” (2401, 2404-2406).

This work on fats and proteins led to a biochemical generalization concerning the biochemical constituents of the body: The large, complex macromolecules are constantly involved in rapid chemical reactions with their smaller component units, a continuing and constant process of degradation and resynthesis. This generalization overthrew the prevailing opinion that the dietary constituents are used only for repair and for energetic purposes.

James A. Doull (US) carried out clinical trials on the efficacy of using diasone (Diamidin), 4-4’ diaminodiphenyl sulfone, and dihydrostreptomycin for the treatment of leprosy. It is also called DDS or dapsone. The trials were successful and even today it is still used in combination with antibiotics for treatment of Hansen’s disease (leprosy) (729).

Albert Francis Blakeslee (US), Amos G. Avery (US), and Albert Levan (SE) discovered that the plant alkaloid colchicine—isolated from autumn crocus and other members of the genus Colchicum—could induce mutations in cells by interfering with cell division. It prevented chromosomes, once doubled, from being partitioned into daughter cells (219, 1635).

James Frederick Bonner (US) and James English, Jr. (US) discovered a plant wound hormone, which stimulates cell division. They called it traumatin. Chemically it is 1-decene-1, 10-dicarboxylic acid (251).

Don C. Zimmerman (US) and Carol A. Coudron (US) determined that the wound hormone results from a non-enzymatic oxidation of 12-oxo-trans-10-dodecenoic acid, the first compound in the jasmonic acid pathway (3099).

Henry Arnold Lardy (US) and Paul H. Phillips (US) gave the first clear evidence that 2,4-dinitrophenol interferes with the energy-coupling mechanism with the result that oxidation and glycolysis run rampant, while the energy is lost as heat rather than being conserved for work (1594).

Jacques Lucien Monod (FR) proved that agents, which uncouple oxidative phosphorylation, such as 2,4-dinitrophenol, completely blocked the shift from one substrate to the other. This suggested that the shift required synthesis of another enzyme thus requiring considerable energy (1907).

M.I. Nakhimovskaia (RU) was the first to survey the soil for the presence of actinomycetes antagonistic to bacteria. Of 80 isolates studied, 47 could suppress bacterial growth, but only 27 released antagonistic substances into the medium (1967).

Selig Hecht (PL-US) explained that when the eyes are exposed to light visual purple (rhodopsin) is converted into a nerve stimulator and retinene (retinal) (yellow). New visual purple is synthesized from vitamin A (retinol) obtained from the blood stream (1194).

Thaddeus Robert Rudolph Mann (PL-GB) found that in plant tissues the highest concentration of hematin (iron protoporphyrin) occurred in the meristematic tissues and concluded that these higher concentrations correlated with higher metabolic activity (1761, 1762).

Aleksandr Evseyevich Braunstein (RU) and Maria Grigorievna Kritzmann (RU) reported that in minced pigeon-breast muscle, the alpha-amino group of glutamic acid is transferred reversibly to pyruvic acid (to form alanine) or to oxaloacetate (to form aspartic acid) thus effecting a transamination reaction. This discovery provided a metabolic linkage between the ornithine cycle and the citric acid cycle (287).

Philip Pacy Cohen (US) pointed out problems of earlier papers on transamination then refined and made precise the study of transamination. Cohen originated the term transaminase for the enzyme catalyzing transamination (494, 495).

Herman Moritz Kalckar (DK-US), Vladimir Aleksandrovich Belitzer; Vladimir Aleksandrovich Belitser (RU), and Elena T. Tsibakova; Elena T. Tsibakowa (RU) independently supplied evidence that phosphorylation is coupled to respiration. They showed that when various intermediates in the tricarboxylic acid cycle were oxidized by buffered suspensions of freshly minced liver, kidney, or muscle tissue, inorganic phosphate present in the medium disappeared. Concomitantly, there was an increase in the concentration of organic phosphate compounds, such as glucose 6-phosphate and fructose 6-phosphate, whose phosphate groups are derived from ATP. When the tissue suspensions were deprived of oxygen or poisoned with cyanide, uptake of inorganic phosphate did not take place. It was therefore concluded that phosphorylation of ADP is coupled to aerobic respiration as a mechanism for energy recovery.

Belitzer and Tsibakova reported that the phosphorylation of creatine in pigeon heart muscle is coupled to the oxidation of any one of a number of metabolites (e.g., citrate, alpha-ketoglutarate, succinate, pyruvate, lactate, malate, fumarate) and that approximately two molecules of creatine phosphate are synthesized per atom of oxygen consumed (170, 1391, 1393, 1397).

Albert Imre Szent-Györgyi (HU-US) drawing on the earlier observations of Torsten Ludvig Thunberg (SE), Federico Battelli (IT), Lina Salomonovna Stern (LT-CH) and others assembled a logical sequence for the cellular oxidation of succinate: succinate—fumarate—malate—oxaloacetate. Especially significant was Szent-Györgyi’s observation that adding small amounts of oxaloacetate or malate to minced muscle suspensions evokes the utilization of an amount of oxygen far beyond that required to oxidize the added dicarboxylic acid to CO2 and water. From this and other experiments Szent-Györgyi concluded that these acids stimulate the oxidation of some endogenous substrate in the tissue, presumably glycogen, one molecule of malate or oxaloacetate promoting the oxidation of many molecules of the endogenous substrate (2675).

Carl Martius (DE) and Franz Knoop (DE), somewhat later, found that citrate is enzymatically oxidized to succinate by animal tissues in the sequence: citrate—alpha ketoglutarate—succinate (1789).

Hans Adolf Krebs (DE-GB), William Arthur Johnson (GB), and Leonard V. Eggleston (GB) observed that citric acid exerts a catalytic effect on the respiration of minced pigeon-breast muscle and that citrate is successively converted to alpha-ketoglutarate and succinate, and that oxaloacetate is converted into citrate by the addition of two carbon atoms from an unidentified source. From their conclusions and those of prior workers like Franz Knoop (DE), Carl Martius (DE), and Albert Imre Szent-Györgyi (HU-US) they proposed a citric acid cycle: citrate — isocitrate — oxalosuccinate — alpha-ketoglutarate — succinate — fumarate — malate —oxaloacetate — citrate (1518, 1522). This cycle has been found to exist in virtually all plants, animals, and aerobic microorganisms (1517) and has been called tricarboxylic acid cycle, citric acid cycle, and Krebs cycle.

Robert A. Fulton (US) and Horatio C. Mason (US) produced the first evidence for the absorption and translocation of a bulky insecticidal molecule foreign to the plant, when they found that derris applied to the first two leaves of bean plants reduced the attack by the Mexican bean beetle (Chrysomelidae) on leaves subsequently produced (978). This was evidence that the insecticide had spread to become systemic.

Conrad Arnold Elvehjem (US), Robert James Madden (US), Frank Morgan Strong (US), and Dilworth Wayne Woolley (CA-US) demonstrated that lack of sufficient nicotinic acid (vitamin B3 or nicotinamide) in a dog’s diet leads to a disease called black-tongue (820-822). Pellagra is the human equivalent of black-tongue.

Homer William Smith (US) discovered that since inulin is completely filterable at the glomerulus and not reabsorbed, excreted, or synthesized by the renal tubules it can be used to measure glomerular filtration (2533).

Kenneth Vivian Thimann (GB-US) and Frits Warmolt Went (NL-US) suggested that depending on its concentration auxin might produce inhibitory effects in one tissue and stimulation in another, different tissues being characterized by a series of overlapping optimal concentration curves (2711, 2945).

Edward Calvin Kendall (US) and Dwight Joyce Ingle (US) characterized the relation between the adrenal gland and salt and water metabolism, a phenomenon that subsequently became the basis for a bioassay system that led to the recognition that the adrenal cortex secretes a mineralocorticoid hormone (aldosterone) (1430).

Dwight Joyce Ingle (US) and Edward Calvin Kendall (US) found that administration of adrenalcortical extracts or purified glucocorticoids to intact rats causes atrophy of the adrenal glands. Adrenal atrophy could be avoided by simultaneous administration of pituitary extracts (1332, 1335).

Dwight Joyce Ingle (US), Choh Hao Li (CN-US), and Herbert McLean Evans (US) established that the changes in adrenal size and activity are mediated by the pituitary hormone adrenocorticotropin (1334, 1336, 1337). The elucidation of the feedback mechanism between the adrenal cortex and the pituitary became the model for similar studies.

Alan Lloyd Hodgkin (GB) demonstrated the dependence of nerve conduction on the electronic spread of depolarization induced by local current from the region of the action potential to that ahead of it to cause enhanced excitability and excitation (1247, 1248).

Edward Holbrook Derrick (AU), Frank Macfarlane Burnet (AU), and Mavis Freeman (AU), worked on an outbreak of febrile disease among abattoir workers, described Q fever (Nine-Mile Fever) and Derrick designated Rickettsia burnetii (Coxiella burnetii) as the etiological agent (349-352, 678, 679). The Q stands for query and not Queensland as some writers have reported.

Gordon E. Davis (US) and Herald Rea Cox (US) identified a new rickettsial disease, which they called Nine Mile Fever (named for Nine Mile Creek where the ticks were collected). It is synonymous with Q fever (617).

Fred R. Beaudette (US) and Charles B. Hudson (US) were the first to isolate coronavirus. The source was chickens with infectious bronchitis (154).

David Arthur John Tyrrell (GB) and M.L. Bynoe (GB) used cultures of human ciliated embryonal trachea to propagate the first human coronavirus in vitro (2759).

Jane Parry (GB) reported that severe acute respiratory syndrome (SARS) is likely caused by a strain of coronavirus (2043). It was later called SARS-Associated Coronavirus (SARS-CoV).

Gilbert Julias Dalldorf (US), Margaret Douglass (US), and Horace Eddy Robinson (US) demonstrated the ability of one virus to modify the course of infection by another (infection with lymphocytic choriomeningitis virus protected monkeys from infection by poliomyelitis) (592-595).

Thomas Milton Rivers (US) devised a set of postulates, similar to Koch’s, which were very useful in establishing the causal role of a virus in disease. River’s postulates, applicable to both animal and plant viruses, can be stated as follows:

1) The viral agent must be found either in the host’s body fluids at the time of the disease or in the cells showing specific lesions.

2) The viral agent obtained from the infected host must produce the specific disease in a suitable healthy animal or plant or provide evidence of infection in the form of antibodies (substances produced by vertebrates in response to a virus) against the viral agent. It is important to note that all host material used for inoculation must be free of any bacteria or other microorganisms.

3) Similar material from such newly infected animals or plants must in turn be capable of transmitting the disease in question to other hosts (2252).

Arthur Quinton Wells (GB) discovered and characterized the acid-fast bacillus Mycobacterium microti as the cause of an epizootic, chronic infection of the field vole, i.e., vole tuberculosis (2942).

Robert Lee Hill (GB), Fay Bendall (GB), and Ronald Scarisbrick (GB) discovered that light-induced oxygen evolution could be observed in cell-free granular preparations extracted from green leaves. Illumination of such preparations in the presence of artificial electron acceptors, such as ferricyanide or reducible dyes, caused evolution of oxygen and simultaneous reduction of the electron acceptor —this later became known as the Hill reaction. Carbon dioxide was apparently not required, nor was it reduced to a stable form that accumulated, suggesting that the photoreduction of carbon dioxide to hexose is a later step in photosynthesis. Electrons are being induced to flow away from water molecules to an acceptor, thus yielding molecular oxygen from the water. Yet in animal tissues electrons arising from organic substrates flow toward molecular oxygen, which is reduced to water. Clearly, the direction of electron flow is opposite to that in respiration. The energy of this reversed electron flow, which takes place only on illumination, comes from the absorbed light (1231-1236). The 1960 paper was the first to describe a ‘Z’-scheme for the two light reactions of photosynthesis.

John Burdon Sanderson Haldane (GB-IN) introduced the concept of genetic load which was defined as the proportion of the population that die each generation as a result of the action of selection on a genetic system (1129).

Tracy Morton Sonneborn (US) demonstrated the mechanism for inheritance of mating type in Paramecium aurelia. He determined that a single gene controlled mating type. This was the first gene to be demonstrated in the ciliates (2561-2564).

Gladwyn Kingsley Noble (US) and A.H. Schmidt (US) discovered that two groups of snakes, the pit vipers (Crotalidae) and the boas (Boidae) use thermal radiation from a warm-blooded animal such as a mouse to guide their striking motion (1990).

Frank Fraser Darling (GB) did a classic field study of red deer and wrote A Herd of Red Deer. This research would be instructive reading for any aspiring field biologist (612).

Theodosius Grigorievich Dobzhansky (Ukrainian-US) authored Genetics and the Origin of Species in which he concluded that genetic mutations generate numerous variations thus providing the raw material for natural selection. This book also made a deep impression on naturalists by relating systematics to genetics (703).

Walter Michel (DE) was the first to produce artificial heterokaryons. He fused plant protoplasts from different species and genera (1887).

William Jacob Robbins (US), Mary A. Bartley (US) and Frederick Kavanagh (US) showed that vitamin B1 (thiamine) promotes the growth of tomato root tips and fungi in culture (2256, 2257). This was the first time that a vitamin was shown to be necessary for plant or fungal growth.

William Jacob Robbins (US) and Mary Stebbins (US), had by 1949, kept tomato roots through 131 consecutive passes in a solution of mineral salts, cane sugar, and thiamine or thiazole. A period of over twenty years!

Charles Drechsler (US) discovered that the fungus Arthrobotrys dactyloides throttles its nematode prey with nooses of three cells held out on a short stalk. A nematode worm passing through one of these traps triggers its closure. The cells triple in volume in a tenth of a second, constricting and ensnaring the worm for consumption (732).

Alfred Edwards Emerson (US), based on his work with termites, wrote the first of many articles defending the use of behavioral traits as taxonomic characters (824).

Per Fredrik Thorkelsson Scholander (SE-NO-US), Laurence Irving (US), Wilhelm Bjerknes (NO), Edda Bradstreet (US), Stuart W. Grinnell (US), Herschel V. Murdaugh, Jr. (US), Bodil M. Schmidt-Nielsen (DK-US), J.W. Wood (US), William L. Mitchell (US), Harold Theodore Hammel (US), David Hugh LeMessurier (AU), Edvard A. Hemmingsen (NO-US), and Walter F. Garey (US) investigated the physiology of deep diving mammals and found that: seals exhale prior to a dive, thus decreasing the nitrogen content of their lungs and avoiding the “bends.” The oxygen-carrying capacity of the blood is much greater in a seal than in man. The seal’s blood volume is relatively large, and both blood and muscles contain much larger amounts of hemoglobin, and thus hold more oxygen, than in mammals in general. A seal’s most characteristic response to an experimental dive is to slow the heart down to a few beats per minute (diving bradycardia is typical of all animals investigated; that is mammals, birds, reptiles, amphibians, and even fishes which had been taken out of water); the blood is diverted to the most vital organs, notably the central nervous system and eyes. The muscles, which are able to function anaerobically through the formation of lactic acid, receive no blood and thus acquire an oxygen debt that is repaid when oxygen is again available at the termination of the dive.

For these investigations Scholander developed new methods for continuous recording of the respiratory metabolism of diving animals (1342, 1343, 1948, 2408-2418).

Julia Bell (GB) and John Burdon Sanderson Haldane (GB) described the first example of linkage in humans in X-linked pedigrees transmitting both hemophilia and color blindness (171).

Jacob Furth (US) and Morton Kahn (US) were the first to allude to cancer stem cell (CSC) or tumor-initiating cell principles. Using cell lines, they provided the first quantitative assay for the assessment of the frequency of the malignant cell maintaining the hematopoietic tumor. They showed that a single leukemic cell is able to transmit the systemic disease when transplanted into a mouse (981).

Robert Bruce (CA) and Hugo Van der Gaag (CA) used the spleen colony-forming assay (CFU-S) to show that only a small subset of primary cancer tissue is able to proliferate in vivo (323).

William Warrick Cardozo (US) concluded that sickle cell anemia is inherited following Mendelian law and is more frequent among black people or people of African descent (402).

Samuel Soskin (US) and Rachmiel Levine (PL-CA-US) espoused the concept of a hepaticthreshold for glucose, defined as the blood glucose level atwhich glucose production and utilization by the liver exactlybalance each other. They believed that the hepatic thresholdfor glucose is elevated in diabetes and lowered by insulin (2570).

Ludvig G. Browman (US) showed that the exposition of rats to continuous light interrupts the estral cycle inducing the state of persistent estrous (309).

Virginia Mayo Fiske (US) reported on the effect of light on sexual maturation, estrous cycles, and anterior pituitary in the rat (914).

Raphael Issacs (US), using careful cytological study of the cell types in lymphosarcoma leukemia, found that the cells are not lymphocytes, but lymphosarcoma cells, so that the condition is true lymphosarcoma cell leukemia (1345).

Jan Gosta Waldenström (SE) described over one hundred patients with acute intermittent porphyria (AIP), most of who originated from a small village in Northern Sweden (2876). AIP is characterized by recurrent episodes of abdominal pain, vomiting, constipation, hypertension, tachycardia, and neurologic involvement including muscle weakness, mental changes, and even seizures.

Since this early observation, specific inherited deficiencies of enzymes within the heme synthetic pathway have been delineated that allow improved understanding of classification, pathogenesis, and genetic screening.

James Wenceslas Papez (US) published work on the limbic circuit and conceived a mechanism of emotion (hypocampo-thalamo-cingulate-hippocampal circuit) associated with this region of the brain (2035). Limbic means border.

Paul D. MacLean (US) coined the phrase limbic system and distinguished three limbic circuits based on function; emotions related to self-preservation (amygdala and hippocampus), emotions related to pleasure (cingulate gyrus and septum), and emotions related to social cooperation (parts of the hypothalamus and anteriorthalamus) (1746, 1747).

Paul D. MacLean (US) proposed that our skull holds not one brain, but three, each representing a distinct evolutionary stratum that has formed upon the older layer before it, like an archaeological site: the triune brain. The three levels are 1) the Reptilian Brain, 2) the Limbic System (Paleomammalian brain), and 3) the Neocortex (Neomammalian brain) (1748).

Tracy J. Putnam (US) and H. Houston Merritt (US) were the first to discover that phenytoin (PHT) (also diphenylhydantoin) is a therapeutically effective substance when it counteracts electrically induced hyperexcitability and convulsions in the cat (1852, 2144).

Riojun Kinosita (JP-US) found that liver tumors could be readily induced by ingestion of dimethylaminoazobenzene, a dye known as " butter-yellow " (1452).

Wade H. Marshall (US), Clinton Nathan Woolsey (US), and Archibald Philip Bard (US) used the cathode ray oscilloscope and the evoked potential technique to develop detailed mapping of the somatic sensory area of the cerebral cortex of the cat and monkey (1779, 1780, 3079).

Walter Edward Dandy (US), in 1937, performed he first direct surgical approach and clipping of a cerebral aneurysm (608).

Alfred Wiskott (DE), Robert Anderson Aldrich (US), Arthur G. Steinberg (US), and Donald C. Campbell (US) described a syndrome characterized by a triad of eczema, profound thrombocytopenia, and frequent infections due to immunological deficiency. It is a sex-linked recessive disorder with a defect in both T and B cell function (29, 3039). It is often called Wiskott-Aldrich syndrome.

Thomas Hale Ham (US) established that in chronic hemolytic anemia withparoxysmal nocturnal hemoglobinuria (PNH) the lysis is affected by complement. He demonstrated a dose-response relationship (limited because hemolysis disappears with even very little dilution of serum), and that inhibition or destruction of complement or components of complement abrogated the lytic reaction (1136).

John Heysham Gibbon, Jr. (US) was the first to attempt a bypass of the heart using an external circulation. Partially replacing the circulation between the heart and the lungs, he managed to keep a cat alive in this way for four hours. Two years later, under sterile conditions, 3 out of 13 cats survived for more than 250 days following similar procedures, with the remaining animals living for between 1 and 23 days (1018, 1019). See, J.J.C. LeGallois, 1813, M. von Frey, 1885, and S. Brukhonenko, 1929.

Clarence Dennis (US), Dwight S. Spreng, Jr. (US), George E. Nelson (US), Karl E. Karlson (US), Russell M. Nelson (US), John V. Thomas (US), Walter Phillip Eder (US), and Richard L. Varco (US) reported the first case of open-heart surgery with machine-supported circulation and oxygenation. It was performed on April 1, 1951. This was apparently the first occasion for such an attempt to be made anywhere. The patient was a 4-year old child with a known inter-atrial septal defect who was previously operated upon with hope of repair by closed technique. When an attempt was made to take the patient off perfusion, the patient’s heart could not maintain the circulation, and the patient expired. Postmortem examination revealed that the lesion was not the simple secundum type of defect but rather an atrioventricular canal, a complicated set of anomalies (648).

Forest Dewey Dodrill (US), Edward Hill (US), and Robert A. Gerisch (US) performed the first clinically successful total left-sided heart bypass in a human on July 3, 1952. The machine was used to substitute for the left ventricle for 50 minutes while a surgical procedure was carried out to repair the mitral valve; the patient's own lungs were used to oxygenate the blood (709, 710).

John Heysham Gibbon, Jr. (US) successfully applied extracorporeal circulation in an 18 year old female with an atrial septal defect. Unfortunately he was unable to repeat this success in other humans (1020).

John Heysham Gibbon, Jr. (US), Arthur R.C. Dobell (US), and George B. Voigt (US) reported the closure of interventicular septal defects on dogs during open cardiotomy with the maintenance of the cardio-respiratory functions by a pump oxygenator (1022).

Clarence Walton Lillehei (US), Morley Cohen (US), Herbert E. Warden (US), and Richard L. Varco (US) used controlled cross-circulation to correct a ventricular septal defect in an 11-year-old boy. The boy's anesthetized father served as the oxygenator. Blood flow was routed from the patient's caval system to the father's femoral vein and lungs, where it was oxygenated and then returned to the patient's carotid artery. The cardiac defect was repaired with a total pump time course of 19 minutes. Over the ensuing 15 months, Lillehei operated on 45 patients with otherwise irreparable complex interventricular defects; most of these patients were less than 2 years old. Although cross-circulation was a major advance, it was not adopted for widespread use because it posed a serious risk to the "donor" (1670).

Clarence Walton Lillehei (US) and Richard A. DeWall (US), in 1955, advanced the concept of a heart-lung machine. They called it a helix reservoir bubble oxygenator, which bubbled oxygen through the blood during the operation (1671).

Arne Torkildsen (NO), in 1937, performed the first ventriculocisternostomy to relieve obstructive hydrocephalus. This is the surgical formation of an opening between the ventricles of the brain and the cerebellomedullary cistern (2745).

Andrew W. Contratto (US) and Samuel A. Levine (US) studied 180 cases of aortic stenosis, unassociated with other significant valve disease, 53 of which were examined post mortem. Among the cases an early history of rheumatic fever was common. A loud basal systolic murmur, a systolic thrill near the aortic area, and calcification of the valve were common. Disturbances in conduction such as bundle branch block and auriculoventricular block were common. Angina pectoris occurred in 22.7 % of the cases. There were 21 instances of syncope (527).

William H. Lang (GB) positioned Cooksonia pertonii as the earliest known land-living vascular plant found in England and one of the earliest in the world (1586).

ca. 1938

1938

Richard Johann Kuhn (DE) was awarded the Nobel Prize in Chemistry for his work on carotenoids and vitamins. He was caused by the authorities of his country to decline the award but later received the diploma and the medal.

Corneille Jean Francois Heymans (BE) was awarded the Nobel Prize in Physiology or Medicine for the discovery of the role played by the sinus and aortic mechanisms in the regulation of respiration.

William Thomas Astbury (GB), and Florence Ogilvy Bell (GB) presented the first x-ray diffraction pictures of DNA. They were of calf thymus DNA sent to them by Torbjörn Oskar Caspersson, the Swedish biochemist (78-80).

Max Ferdinand Perutz (AT-GB), John Desmond Bernal (GB), Isadore Fankuchen (US), Michael George Rossmann (US), Ann F. Cullis (GB), Hilary Muirhead (GB), Georg Will (GB), and Anthony C.T. North (GB) were among the first to report the tertiary and quaternary structure of a protein—hemoglobin and chymotrypsin. Perutz began this work as part of his Ph.D. thesis in 1937 (194, 2074-2081).

Edward Charles Dodds (GB) discovered diethylstilbestrol (DES), a powerful synthetic hormone used to treat prostate conditions, to fatten cattle, to treat women at risk for miscarriage and as a morning-after contraceptive (705, 706).

In 1972 the prescribed form of diethylstilbestrol (DES) was proved carcinogenic in adult women as well as in fetuses, when unusual types of endometrial cancer, reminiscent of the adenocarcinomas of the vagina of DES daughters, developed in young women treated with DES for five years or longer.

Arthur Stoll (CH) and Albert Hoffman (CH-US), in 1938, produced lysergic acid diethylamide (LSD) while trying to synthesize a new drug for the treatment of headaches. It is one of the most potent psychoactive drugs known (2644).Later it was shown to block or inhibit the action of the brain’s neurotransmitter serotonin (2097).

David Keilin (PL-GB) and Edward Francis Hartree (GB) described the mechanism of the decomposition of hydrogen peroxide by catalase (1417).

Felix Haurowitz (CZ-US) discovered the drastic change in crystalline shape of deoxyhemoglobin from hexagonal plates to elongated prisms as oxygen is taken up (1182). This is sometimes cited as the first observation of an allosteric reaction.

Lionel Ernest Howard Whitby (GB) reported that 2-(p-aminobenzene sulphonamide) pyridine is chemotherapeutically active in experimental infections in mice against pneumococci of Types I, II, III, V, VII, VIII and especially against Types I, VII, and VIII. It was as active as sulphanilamide against hemoltyic streptococcus and meningococcus (2965).

Maxwell Finland (RU-US), Elias Strauss (US), and Osler L. Peterson (US) reported that the sulfonamide, “Sulfadiazine was used in the treatment of 446 patients with various infections. It appeared to be highly effective in the treatment of…pneumococcic, staphylococcic and…pneumonias; meningococcic infections; acute infections of the upper respiratory tract including sinusitis; erysipelas; acute infections of the urinary tract, particularly those associated with Escherichia coli bacilluria, and acute gonorrheal arthritis…. Toxic effects…were relatively mild and infrequent” (897).

Cornelis Adrianus Gerrit Wiersma (NL-US) identified the lateral giant interneuron as key to triggering the tail flip escape in response to a sharp tap on the animal's abdomen (2984, 2985).

Franklin B. Krasne (US) made one of the first attempts to analyze the synaptic basis for the release of an animal's fixed action pattern. In this case the neural controls of the crayfish escape response. More complex than a simple reflex, this response results from a 'decision' reached by the animal in response to a specific sort of stimulus. Once triggered, the response orchestrates the behavior of the animal's entire body. These escape behaviors are often found to be subject to simple forms of learning, including habituation, dishabituation and sensitization. For crayfish escape, the relevant question was whether habituation of the escape response occurred because the afferent pathway to the lateral giant interneuron, or the lateral giant interneuron itself, became less excitable with repeated stimulation, or because increasingly strong inhibition was imposed on the lateral giant interneuron circuit from elsewhere in the nervous system.

Krasne completed the general outline for the afferent path to the lateral giant interneuron, and therefore for the entire escape circuit. This was one of the first, if not the first, polysynaptic circuits for a fixed action pattern that had been so described. Second, he demonstrated that much, but not all, of behavioral habituation of the escape response could be accounted for by synaptic depression within one limb of the afferent path that carries nervous signals to the lateral giant interneuron (1501).

Archibald Vivian Hill (GB) found that, even in "isometric" contractions, the muscle fibers initially shorten. He proposed that skeletal muscles have two distinct components in series with each other: a contractile component that shortens when stimulated and an elastic component that lengthens under tension. Hill proposed an empirical relation for the force-velocity curve that emphasized the hyperbolic form of the data. This equation is still commonly used today: (force + a)(velocity + b) = (forcemax + a)b, where a and b are constants. The functional importance of the Hill equation is that it allowed scientists to clearly distinguish between slow-twitch and fast-twitch muscles and, using this relationship, develop force-power curves and determine peak power (1228).

John T. Manter (US) created an elegant force plate design which stands out from others because it was the first to record forces in three axes – vertical, fore–aft and lateral – and therefore is the prototype of the modern force plate used in biomechanics research as well as clinical orthopedics. His work appears to be the first to combine simultaneous measurements of individual foot forces and film to use the modern inverse dynamics approach to estimate the muscle forces acting at individual joints and for measuring mechanical work. Manter's inverse dynamics analysis of cat walking led him to conclude that some muscles may act isometrically (1765).

Herman Moritz Kalckar (DK-US) provided evidence for the production of phosphoenolpyruvate (PEPA) from fumaric or malic acids, observations that later provided an important clue to the mechanisms involved in the formation of glucose from non-carbohydrate sources in animal tissues (1392).

Carl Ferdinand Cori (CZ-US), Gerty Theresa Cori, née Radnitz (CZ-US), Sidney P. Colowick (US) and Gerhard Schmidt (DE-US) recognized that ATP is required to phosphorylate glucose and thus energize it for the biosynthesis of glycogen. They also discovered that if glycogen is broken down it is not hydrolyzed to glucose units but rather is converted to units of glucose-1-phosphate by phosphorylase in a readily reversible reaction. (Later it was discovered, by others, that the glycogen synthesis reaction is uridine-5’-triphosphate + glucose-1-phosphate yieldsuridine diphosphate glucose (UDPG), which yieldsglycogen in the presence of glycogen synthetase). They demonstrated the in vitro synthesis of amylose (the linear alpha 1,4-glycosidically linked polysaccharide) from glucose-1-phosphate. During breakdown the glucose-1-phosphate is converted to glucose-6-phosphate and this in turn undergoes other changes through a whole series of phosphate-containing compounds. Painstakingly the Coris detected these and fitted them into the proper niches of the breakdown course (546, 547, 550). Wilhelm Kiessling (DE) made very similar observations (1440, 1441).

Charles Samuel Hanes (CA), in 1940, would show that higher plants are capable of carrying out the same reactions (1150).

William Cumming Rose (US) determined that ten amino acids are essential in the diet of the rat and dog (histidine, isoleucine, leucine. threonine, lysine, methionine, phenylalanine, tryptophan, valine, and arginine). The rat was found to survive in the absence of arginine but its growth was suboptimal (2276, 2288).

James Gordon Horsfall (US), Robert O. Magie (US), and Ross F. Suit (US) discovered that the Bordeaux mixture harms tomatoes by closing the leaf pores, weakening the cuticle around the pores, and hardening the lamella within the leaves and stunting the plants (1287).

Peter Wilhelm Joseph Holtz (DE), Rudolf Heise (DE), and Kathe Lüdtke (DE) determined that epinephrine (adrenaline) is made from norepinephrine (noradrenaline) in the chromaffin cells of the adrenal medulla (1270).

Johannes Van Overbeek (US) reported that certain nongeotropic mutants in maize did not show the usual inequality of auxin distribution (2786).

Rudolf Signer (CH), Torbjörn Oskar Caspersson (SE), and Einar Hammarsten (SE) reported that the physical properties of calf thymus DNA suggested that the molecule is rod shaped, with a length approximately 300 times its width, and a molecular weight between 500,000 and 1,000,000 (2499).

Albert Edward Gillam (GB) and Isidore Morris Heilbron (GB), William Edward Jones (GB), Edgar Lederer (FR), and Franz H. Rathmann (FR) discovered that vitamin A (retinol) in the retinas of fresh water fishes differs from that found in other animals. This form is called vitamin A2 (1029, 1616).

W. William Sebrell (US) and Roy F. Butler (US) used canine experiments to show that some pellagra patients who resisted treatment with nicotinic acid were in fact simultaneously suffering from riboflavin (vitamin B2) deficiency (2428). Joseph Goldberger (SK-US) and George A. Wheeler (US) had called this condition pellagra sine pellagra but did not appreciate its underlying cause.

Wilhelm Sigmund Feldberg (DE-GB) and Charles Halliley Kellaway (GB) discovered that cobra venom contains a substance that causes the contraction of smooth muscle in the guinea pig. They determined that it is distinct from histamine, another known factor in inflammatory reactions. Relative to histamine, this new mediator has a longer duration of action and thus was called the slow reacting substance (SRS) (865).

Walter E. Brocklehurst (GB) refined its name to "slow reacting substance of anaphylaxis," or SRS-A (303). See Dahlen, 1980.

Robert C. Murphy (US) Sven Hammerstrom (SE), and Bengt Samuelsson (SE) elucidated the structure of the "slow reacting substance of anaphylaxis" (SRS-A) as a derivative of arachidonic acid, leukotriene (1949).

Georg Charles de Hevesy (HU-SE), Jakub (Jacob) Karol Parnas (PL), Tadeusz Baranowski; Tadeush Baranowski (PL), A. Jerzy Gutke (PL), Pawel Ostern (PL), and Tadeusz W. Korzybski (PL) conducted experiments with tissues, eggs, milk, and yeast fermentations using synthetic radioactive adenylic acid, in which it was possible to trace radioactive phosphorus. After a period of incubation a considerable portion of the active phosphorus was found in the sugar phosphoric acid esters fraction. Evidence indicated that this also occurs in bacteria, muscle, and yeast cells (626, 1495, 2039). These experiments are likely the first to use radioactive phoshorus in biological studies.

Wilhelm Kiessling (DE) and Otto Fritz Meyerhof (DE-US) found that adenylic acid and its allied phosphates act as coenzymes in the transfer of phosphates from phosphopyruvic acid to glucose (1442, 1443). Among these adenosine nucleotides are: adenylic acid, adenosine diphosphate and adenosine triphosphate, diadenosine pentaphosphoric acid, diadenosine tetraphosphoric acid, and the pyrophosphate. All apparently function as phosphate carriers in cellular glycolysis.

Otto Heinrich Warburg (DE) discovered flavoproteins on the basis of simple observations on lactobacilli that lack the red cytochromes. On exposure to air the intact cells become yellow. He isolated dehydrogenases, flavoproteins, and identified their coenzymes (2895).

Otto Heinrich Warburg (DE) and Walter Christian (DE) working with a preparation of D-amino oxidase isolated a flavin derivative, which would later be shown to be flavine-adenine-dinucleotide (FAD) (2903).

Erwin Haas (US) showed that this FAD is also the prosthetic group of a flavoprotein isolated from yeast (1119).

Hans W. Doerr (DE) stated that herpes simplex virus infection in man resulted from the endogenous production of a virus-like agent by the cell under the influence of certain stimuli, and were not caused by exogenous infection. Once the agent had been produced, it would act on the cells of susceptible animals (not man) as a true virus (712).

Frank Macfarlane Burnet (AU) and Stan W. Williams (AU) stated that ‘Herpes simplex infections, however, once contracted, seem to persist for life. The virus remains for the most part latent; but under the stimulus of trauma, fever, and so forth it may at any time be called into activity and provoke a visible herpetic lesion” (358).

Stephen Bartlett (GB), Anda G. Cotton (GB), Isaac Walker Rupel (US), Gustav Bohstedt (US), Edwin Bret Hart (US), Edwin C. Owen (GB), James Andrew Buchan Smith (GB), and Norman Charles Wright (GB) clearly established that bacteria of the rumen synthesize protein from nonproteinaceous material and are capable of obtaining nitrogen from sources such as urea. Significant amounts of protein is made available to the ruminant when the bacteria die and are digested (130, 2016, 2324).

Torbjörn Oskar Caspersson (SE), Jack Schultz (US), Lennart Aquilonius (SE), and Jean Louis Auguste Brachet (BE) collected considerable evidence about the location of the nucleic acids within cells. Their work indicated that there is a correlation between high levels of protein synthesis and high levels of RNA synthesis. Caspersson also noted that most of the cytoplasmic RNA is concentrated in particles (271, 272, 412-418, 2424).

Edgar G. Anderson (US) and Leslie Hubricht (US) developed the concept of introgressive hybridization—usually termed “introgression”—and gave it its name. As the name implies, introgression refers to the gradual infiltration of germplasm of one species into another through repeated backcrossing (52).

Theodosius Grigorievich Dobzhansky (RU-US) and Alfred Henry Sturtevant (US) published the first account of the use of inversions in constructing a chromosomal phylogenetic tree (704).

William Ernest Castle (US), from his genetic studies in mice, concluded that albinism has no influence on body size (422).

Marcus Morton Rhoades (US) discovered the Dotted mutator gene in maize. It was found on a single ear of corn where it produced a phenotype of variegated endosperm characterized by purple dots on a colorless background (2221).

Barbara S. Burks (US) recorded the first case of autosomal linkage in man. It involved tooth deficiency and hair color (345).

Warren Weaver (US) is credited with being the first person to use the phrase molecular biology in its modern context. In his 1938 report to the Rockefeller Foundation he said, "Among the studies to which the Foundation is giving support is a series in a relatively new field, which may be called molecular biology” (2925). See, Karl Friedrich Wilhelm Ludwig, 1858.

Harry Plotz (US) grew the measles virus in the Macacus rhesus monkey, transferred it to chick embryo culture, then induced the disease in monkeys (2115). This work essentially proved the viral etiology of measles.

John Franklin Enders (US) and Thomas C. Peeples (US) grew the measles (rubeola) virus in several cell lines including human kidney tissue culture and observed that it induced the formation of multinucleated syncytia with a foamy appearance in cell culture. It was during these experiments that foamy virus (a retrovirus) was discovered (837).

Erich Traub (DE-US) showed that if you inject lymphocytic choriomeningitis virus into embryonic mice in utero, they grow up without making antibodies to it, even though it is very foreign. Mice infected as adults give a normal immune response (2752). Ray David Owen (US) would later call this phenomenon tolerance. See Owen, 1945.

Venezuelan equine encephalitis virus (VEEV), Eastern equine encephalitis virus (EEEV), and Western equine encephalitis virus (WEEV) are members of the genus Alphavirus (family Togaviridae) transmitted by mosquitoes. Enzootic strains of EEEV and WEEV typically circulate among birds, whereas, VEEV circulates among rodents in forest or swamp habitats. Epizootic strains of VEEV, typically belonging to subtypes IAB and IC, circulate among equine amplification hosts in agricultural habitats, but are not known to persist in permanent foci.

C.E. Beck (US), Ralph W.G. Wyckoff (US), Vladimir Kubes (US), and Francisco A. Ríos (US) were first to isolate the etiological agent of Venezuelan equine encephalitis (VEE). It came from specimens obtained during an equine epizootic in Venezuela in 1936 (155, 1530).

Leroy D. Fothergill (US), John Holmes Dingle (US), and Jacksolt Cabot Fellow (US) confirmed birds as playing a role in the transmission cycle of EEEV (932).

Beatrice F. Howitt (US) isolated the virus of equine encephalitis from the brain of a child (1300).

William Trager (US) was the first to successfully grow an arbovirus (equine encephalomyelitis) in insect tissue culture. He maintained fragments of tissue from the mosquito, Aedes aegypti for two to three weeks depending upon the tissue (2747).

Beatrice F. Howitt (US) isolated WEEV from a man infected with it during an epidemic in California. This proved that humans are susceptible (1301).

Rebecca R. Rico-Hesse (US), John T. Roehrig (VE), Dennis W. Trent (VE), and R.W. Dickerman (VE) reported that subtype IE VEEV strains have historically been considered enzootic and the mosquito Culex (Melanoconion) taeniopus is the proven enzootic vector for enzootic strains of this subtype (2240). Epizootic IAB and IC VEEV strains are thought to periodically emerge and then undergo extinction when they kill or immunize most equids.

Christina Ferro (CO), Jorge Boshell (CO), Abelardo C. Moncayo (US), Marta Gonzalez (CO), Marta L. Ahumada (CO), Wenli Kang (US), and Scott C. Weaver (US) found that enzootic and epizootic VEEV strains typically use mosquitoes from different species as vectors. Enzootic strains are believed to be transmitted almost exclusively by mosquitoes of the Spissipes section of the subgenus Melanoconion within the genus Culex (891).

William Reisen (US) states that Culex tarsalis is the most important mosquito vector of arboviruses in western North America, responsible for maintenance, amplification and epidemic transmission of St. Louis and western equine encephalitis viruses in irrigated and riparian habitats. This species is also a vector of Llano Seco, Turlock, Gay Lodge, and Hart Park viruses, and several species of avian malaria. Cx. tarsalis is an efficient experimental vector of Japanese and Venezuelan equine encephalitis viruses. Culex tarsalis appears to be the most important vector of WEEV with a variety of mammals as incidental hosts (2218).

There is currently a VEEV vaccine available for both humans and horses. The live attenuated vaccine known as TC-83 is a strain of VEEV that was passed 83 times in guinea pig heart cells. There is also an inactivated form of the vaccine known as C-84 derived from the TC-83 strain. Currently only the C-84 vaccine is licensed for use in horses in the U.S. although countries such as Mexico and Colombia still produce the live vaccine for horses.

John Franklin Enders (US), Thomas Huckle Weller (US), and Frederick Chapman Robbins (US) were the first to grow poliovirus in high titer in cell culture. They used human embryonic extraneural tissue (836, 838, 2941).

Hilary Koprowski (PL-US), George A. Jervis (US), and Thomas W. Norton (US) created the world's first polio vaccine, based on oral administration of attenuated poliovirus. In researching a potential polio vaccine, they had focused on live viruses that were attenuated (rendered non-virulent) rather than on killed viruses. They developed the polio vaccine by attenuating the virus in brain cells of the cotton rat (Sigmodon hispidus), a New World species susceptible to polio. They then conducted the first human trial of his attenuated oral poliovirus vaccine, first treating themselves, then at a New York State facility for intellectually disabled children and children with epilepsy (1489).

Jonas Edward Salk (US) prepared a vaccine of chemically inactivated poliovirus (2345-2348). Why this vaccine was chosen for widespread use in lieu of either the Koprowski or Sabin vaccines is interesting.

Albert Bruce Sabin (PL-US) developed a polio vaccine containing live attenuated viruses from the three known strains of poliovirus. He tried the vaccine on himself first then on prison volunteers. The vaccine did not displace the Salk vaccine until 1960 when its use abroad on more than 100 million people made it apparent that it was superior (2339, 2340).

Chief Medical Officer (GB) reported jaundice in a small group of individuals who had received injections of measles convalescent serum (2005). This very likely represents the first recorded cases of serum hepatitis.

Bodo van Borries (DE), Ernst August Friedrich Ruska (DE), Helmut Ruska (DE), and Gerhard Piekarski (DE) applied the electron microscope to the study of bacteria and viruses for the first time (2094-2096, 2775, 2776).

Edgar William Todd (GB) discovered that streptococci produce at least two different hemolysins, streptolysin O and streptolysin S (2738).

Rodolfo Robles (GT) proved that Mal del Pinto o Carate is caused by a spirochete in the genus Treponema. ref

M. Ruiz Castañeda (MX) showed that large numbers of Rickettsiae mooseri appear in the lungs of rats following intranasal inoculation (420).

Herald Rea Cox (US) described the successful cultivation of rickettsia in the yolk sac of the developing chick embryo (561). The family Coxiellaceae and the genus Coxiella, which contain the organism that causes Q fever, are named for him.

Samuel Rickard Christophers (GB) and James D. Fulton (GB) were the first to investigate the metabolism of malarial parasites (458).

Sterling Howard Emerson (US) studied the self-incompatibility system of Oenothera organensis and found that pollen rejection is a function of the style under control of a locus with multiple alleles (830).

Dirkje E. Reinders (NL) found that auxin present in concentrations as low as 1mg/liter stimulated water uptake in potato discs along with an increase in respiration and loss in dry weight (2216).

John Nathaniel Couch (US) discovered that scale insects and the fungus Septobasidium have a mutually reliant relationship, but that together they destroy their host tree (557).

Gottfried Samuel Fraenkel (DE-US) and John W.S. Pringle (GB) showed that the halteres, which replace the second pair of wings in the adult fly, actually function as miniature gyroscopes or balance organs (935).

Hans Spemann (DE) proposed the first cloning experiment, transferring a nucleus from an adult cell to an enucleated egg. In 1928, he used the nucleus from a 16-cell salamander embryo to create an identical twin (2575).

Robert W. Briggs (US) and Thomas J. King (US), working on the frog Rana pipiens, successfully transplanted living nuclei in multicellular organisms. They transplanted blastula nuclei into enucleated eggs, which then developed into normal embryos (301).

John Bertrand Gurdon (GB) transplanted intestinal epithelium-cell nuclei from Xenopus tadpoles into enucleated frog eggs and managed to produce 10 normal tadpoles. The logical consequence of Gurdon's success — that the nuclei of differentiated cells retain their totipotency — provided a key conceptual advance in developmental biology (1103, 1104). This work proved that genes are not lost or changed during cell differentiation — they are just differentially expressed. It became clear that their cytoplasmic environment profoundly influences the genes expressed in a nucleus.

John Bertrand Gurdon (GB) removed the nuclei from fertilized frogs’ eggs, replaced them with nuclei taken from cells of the gut of a single tadpole, and grew a number of frogs with identical genetic constitutions—an animal clone (1105, 1106).

Ian Wilmut (GB), Angelika E. Schnieke (GB), Jim McWhir (GB), Alex J. Kind (GB), and Keith H. Campbell (GB) reported the birth of live lambs from three new cell populations established from adult mammary gland, fetus and embryo, i.e., the lambs were clones of adults. The fact that a lamb was derived from an adult cell confirms that differentiation of that cell did not involve the irreversible modification of genetic material required for development to term. The birth of lambs from differentiated fetal and adult cells also reinforces previous speculation that by inducing donor cells to become quiescent it will be possible to obtain normal development from a wide variety of differentiated cells (3023).

W.W. Ferguson (GB), A.H. Lewis (GB), and S.H. Watson (GB) discovered that trace quantities of molybdenum in the diet of ruminants causes diarrhea. The disease is called teart (887).

Hugh R. Butt (US) and Albert M. Snell (US) reported that their clinical trials indicated a rough inverse relationship between prothrombin levels and coagulation time (377). This led to the use of vitamin K for the treatment of hemorrhage in humans.

Hugh R. Butt (US), Albert M. Snell (US), and Arnold E. Osterberg (US) reported the first successful correction of a vitamin K deficiency in a patient with biliary obstruction (and intraluminal bile acid deficiency). They showed that a crude vitamin K preparation was absorbed and effective only when given together with conjugated bile salts (378).

Maurice Bolks Visscher (US), Raymond C. Ingraham (US), Richard L. Varco (US), Charles W. Carr (US), Robert B. Dean (US), Dorothy Erickson (US), E. Stanton Fletcher, Jr. (US), Harry P. Gregor (US), Marian Sedin Bushet (US), and Dorothy Erickson Barker (US) demonstrated how the intestine handles electrolytes. They established that both anions and cations can be absorbed against a diffusion gradient and that there is a lengthwise gradient of absorption and secretion in the small intestine. They determined that there is a substantial two-way traffic of sodium between blood and lumen of the small intestine and colon and that there is a gradient of decreasing traffic from duodenum to colon.

Chyme is brought to isotonicity and neutrality in the duodenum and upper jejunum by a brisk flow of electrolytes in both directions across the intestinal mucosa. In the ileum there is net absorption of sodium, chloride, and water, with secretion of bicarbonate replacing chloride in the lumen. The colon performs the essential function of maintaining the volume of extracellular fluid by net absorption of the sodium that escapes absorption in the ileum. Ingraham and Visscher presented compelling evidence for the independence of absorptive and secretory fluxes (1338, 2814, 2815).

Henry Hubert Turner (US) described a series of young women with failure of sexual maturation, short stature, and neck webbing. These are the clinical symptoms of what later became known eponymically as Turner’s syndrome.Turner believed the symptoms were due to a defect in the anterior pituitary gland (2756). Today, we know the underlying cause is a 45XO karyotype.

Alexander Benjamin Gutman (US) and Ethel Benedict Gutman (US) pointed out the increased serum activity of acid phosphatase in metastasizing prostate carcinoma and demonstrated the usefulness of measuring serum acid phosphatase levels in the diagnosis and management of patients with prostatic malignancy (1110).

David Bruce Dill (US) noted that reductions in maximal heart rate were as great as 40 to 50 beats per minute at an altitude of 17,500 feet; documented the phenomenon of hemoconcentration during both acute and chronic exposure to high altitude; discovered that the ability of some animals to adapt to high altitudes is more the result of quality than the quantity of their circulating hemoglobin; and showed that one way the human body adapts to higher temperature is by producing more perspiration which contains less salt per unit volume (693).

Sid Robinson (US) in his doctoral dissertation performed the first study ever done describing the effect of age and of strenuous physical training on the aerobic capacity of man. Here for the first time appeared the relationship between age and maximal heart rate as approximately 220 minus age, a finding confirmed many times since (2263).

Jerome W. Conn (US), Louis Harry Newburgh (US), Margaret W. Johnston (US), and Elizabeth S. Conn (US) were among the first to clearly recognize the relationship between obesity and adult-onset diabetes by showing the resumption of normal carbohydrate tolerance after attainment of normal weight in twenty of twenty-one patients (523).

Carl Müller (NO) identified the first patient ever who presented with xanthomas tuberosum and angina pectoris. Müller made a preliminary report of a number of cases in which he expressed that hypercholesterolemia is a frequent and important factor in heart disease, following which several new patients were referred to Müller and in 1939 he published his landmark paper (1933).

Samuel Rosen (US) mobilized the footplate of the stapes to restore hearing in otosclerosis--a procedure attempted by Jean Kessel (DE) in 1876 (2296).

John J. Shea, Jr. (US) developed the modern technique of footplate mobilization, soft tissue grafting of the oval window, and ossicular replacement. Shea is also credited with the first stapedotomy (2459, 2460).

Frederic Edward Mohs (US) developed the Mohs micrographic surgery (MMS) technique in 1938 to remove skin cancer lesions. The Mohs procedure is considered the best method for treating certain types of skin cancer, especially of the head and neck, with cure rates approaching 100% (1902). Occasionally called chemosurgery.

Harvey Williams Cushing (US), Louise Charlette Eisenhardt (US), and Edward B. Schlesinger (US) published their milestone monograph on Meningiomas. Their Classification, Regional Behaviour, Life History and Surgical End Results (585).

The Congress of the United States passed the Federal Food, Drug, and Cosmetic Act of 1938. This act contained provisions dealing with prohibition of economic adulteration of food, mandatory food standards, truth in food labels or labeling, labeling of imitation foods as such, required labeling of foods with manufacturer’s name, address, net quantity of contents, name of the food, and ingredients of the food (521).

Harry Hatton (FR) and Joseph H. Connell (US) investigated the correlation between population age structures and severity of physical factors in the environment. They found that under very harsh conditions the population might be composed of a single dominant year class (524, 525, 1181).

Heinrich Klüver (US) and Paul C. Bucy (US) performed experimental lesion studies in monkeys, which demonstrated that large temporal lobe lesions that included the amygdala resulted in dramatic postoperative changes in behavior, including flattened affect, visual agnosia, hyperorality, and hypersexuality (1464).

South African fishermen, in 1938, netted a coelacanth off the coast of South Africa.It was identified as belonging to a group or subclass of fishes known as the Crossopterygia, or lobe-finned fish, which passed the heyday of their evolutionary history many millions of years ago and were thought to be extinct. It was named Latimeria chalumnae to honor Miss Courtenay Latimer, a museum curator, in East London, South Africa. Almost immediately living specimens were filmed in their native habitat (499, 2534, 2798).

Robert A. Broom (ZA) reported on and named the discovery of Australopithecus robustus: Paranthropus robustus (formerly Parathrops crassidens) by a schoolboy, Gert Terblanche, in 1938 at Kromdraai in South Africa. It had a body similar to that of A. africanus, but a larger and more robust skull and teeth. It existed between 2 and 1.5 million years ago. The massive face is flat or dished, with no forehead and large brow ridges. It has relatively small front teeth, but massive grinding teeth in a large lower jaw. Most specimens have sagittal crests. Its diet would have been mostly coarse, tough food that needed a lot of chewing. The average brain size is about 530 cc. Bones excavated with robustus skeletons indicate that they may have been used as digging tools (306, 307).

“As man is now changing the composition of the atmosphere at a rate which must be very exceptional on the geological time scale, it is natural to seek for the probable effects of such a change. From the best laboratory observations it appears that the principal result of increasing atmospheric carbon dioxide … would be a gradual increase in the mean temperature of the colder regions of the Earth.” Guy Stewart Callendar (388).

“The fungi in their reproduction and inheritance follow exactly the same laws that govern these activities in higher plants and animals.” Bernard Ogilvie Dodge (708).

Adolf Friedrich Johann Butenandt (DE), for his work on sex hormones, and Leopold Stefan Ruzicka (HR-CH), for his work on polymethylenes and higher terpenes, were awarded the Nobel Prize in chemistry. Butenandt was caused by the authorities of his country to decline the award but later received the diploma and the medal.

Gerhard J. Domagk (DE) was awarded the Nobel Prize in Physiology or Medicine for the discovery of the antibacterial effects of prontosil. (Caused by the authorities of his country to decline the award, but later received the diploma and the medal.)

Siemens AG (DE) produced the first commercial transmission electron microscope.

Werner E. Bachmann (US), J. Wayne Cole (US), and Alfred L. Wilds (US) accomplished the total synthesis of equilenin, a sex hormone from pregnant mares. This was particularly significant because it confirmed many of the assumptions about the configuration of the steroid ring structure (93).

A. Calvin Bratton (US) and Eli Kennerly Marshall, Jr. (US) developed a method for the quantitative determination of sulfonamides in blood and tissues. This method was important because it permitted a rational basis for dosage (281).

Samuel M. Ruben (US), William Zev Hassid (RU-GB-US), Martin David Kamen (CA-US), and Don DeVault (US) used the short-lived radioactive carbon, C11, as an indicator, to study the assimilation of C*O2 by barley. They found that leaves kept illuminated or in complete darkness for less than two and one-half hours formed radioactive carbohydrates. Leaves kept in the dark for over two and one-half hours did not form radioactive carbohydrates. This work with carbon 11 paved the way for isotope tracer research (2315, 2317).

Georg Borgström (SE-US) found that plant shoots exposed to ethylene exhibited positive geotropism associated with the predicted auxin distribution. Ethylene must in some way influence the transverse movement of auxin (256).

Paul Jackson Kramer (US) found that, “Most, and possibly under some circumstances all, of the water absorbed by transpiring plants is absorbed as a result of forces set in motion by loss of water in transpiration.” Water absorption in plants occurs slowly by osmotic means at night when transpiration is negligible and results in “root pressure” in the vascular system often leading to formation of droplets around the margins of leaves (guttation). During the day water is absorbed by forces originating in the shoot because of the dehydration caused by transpiration, and these forces extend through the living tissues of the root into the soil water (1498).

Otto Heinrich Warburg (DE) and Walter Christian (DE) isolated an enzyme, glyceraldehyde-3-phosphate dehydrogenase, which catalyzes the oxidation of glyceraldehyde-3-phosphate to 1,3-diphosphoglyceric acid. They demonstrated that this reaction required the presence of inorganic phosphate and oxidized DPN (NAD), which was converted to reduced DPN (NAD) during the reaction. The reduced coenzyme subsequently donated hydrogens to acetylaldehyde to produce ethyl alcohol (2894).

Otto Heinrich Warburg (DE), Walter Christian (DE), and Theodor Bücher (DE), isolated an enzyme which converts 1,3-diphosphoglyceric acid + adenosine diphosphate (ADP) to 3-phosphoglyceric acid + adenosine triphosphate (ATP) (332, 2904). This was a particularly important discovery because for the first time it linked the release of chemical energy by oxidation to the substrate level synthesis of adenosine triphosphate (ATP), i.e., substrate level phosphorylation.

Erwin Paul Negelein (DE) and Heinz Brömel (DE) determined that during glycolysis when glyceraldehyde-3-phosphate is acted upon by glyceraldehyde-3-phosphate dehydrogenase in the presence of inorganic phosphate the immediate product is 1,3-diphosphoglyceric acid (1970, 1971).

John Robert Raper (US) and Arie Jan Haagen-Smit (NL-US) discovered that hormones are used to control sexual behavior in species of Achlya, a common genus of aquatic fungi (2169-2176, 2181, 2195, 2196).

Trevor McMorris (US) and Alma Barksdale (US) isolated and characterized hormone A of Achlya. It was found to be a sterol and renamed antheridiol, the first steroid hormone found in either plants or the fungi (1836).

Daniel Israel Arnon (PL-US) and Perry R. Stout (US) discovered that molybdenum is essential for growth in all plants (72).

George Wells Beadle (US) proposed the "Teosinte Hypothesis," in which maize was domesticated from teosinte by human selection (144).

Paul Mangelsdorf (US) later suggested that maize was the product of hybridization between an undiscovered wild maize and Tripsacum, the "Tripartite Hypothesis" (1759). Most scientists currently support the “Teosinte Hypothesis.”

Frank A. Brown, Jr. (US) and Ona Cunningham (US) demonstrated the influence of the hormone from the sinus gland in the eyestalk of crustaceans on normal viability and ecdysis (311). See, Zeleny, 1905.

George Widmer Thorn (US), Lewis L. Engel (US), Harry Eisenberg (US), Samuel S. Dorrance (US), and Emerson Day (US) found that bilaterally adrenalectomized dogs, fed a constant diet of low sodium and chloride content, may be maintained in excellent condition, by means of the subcutaneous implantation of pellets of crystalline desoxy-corticosterone acetate. This demonstrated that Addison’s disease is due to a deficiency of adrenal cortical hormone (2714, 2715).

William D. Salmon (US) and Ruben William Engel (US) reported that a deficiency of pantothenic acid causes lesions in the adrenal glands of rats (2349).

Alan Lloyd Hodgkin (GB), Andrew Fielding Huxley (GB), Howard J. Curtis (US), and Kenneth Stewart Cole (US) directly measured the action potential within the nerve fiber (cells) (502, 580, 1249). “We have recently succeeded in inserting micro-electrodes into the giant axons of squids…. A small action potential was recorded from the upper end of the axon and this gradually increased as the electrode was lowered, until it reached a constant amplitude of 80-95 mv…. The axon appeared to be in a completely normal condition, for it survived and transmitted impulses for several hours…. These results…prove that the action potential arises at the surface” (1249).

Vladimir Aleksandrovich Belitzer; Vladimir Aleksandrovich Belitser (RU), Elena T. Tsibakova (RU), and Severo Ochoa (ES-US-ES) made the first quantitative measurements of phosphorus and oxygen in the respiratory chain and determined that the P:O ratio is greater than one. Ochoa concluded that the P:O ratio during the oxidation of pyruvate to carbon dioxide is 3 (170, 1397, 2002, 2003).

W.J. Schmidt () gave the first evidence of fibrous organization in the living spindle with his observations of developing sea-urchin eggs made in 1937, and reinterpreted in 1939, with a polarizing microscope (2392).

Shinya Inoué (JP) gave the definitive visual demonstration of the existence of spindle fibers in untreated living cells (1340).

George Otto Gey (US) and Frederick B. Bang (US) were the first to report a cytopathic effect caused by a virus in cell culture. The agent was lymphopathia venera virus (1017).

Morris Frank Shaffer (US) and John Franklin Enders (US) developed a quantitative virus indicator system using counts of foci on the chorio-allantoic membrane of the chick (2444).

Ernest Everett Just (US) wrote The Biology of the Cell Surface (1384).

Johannes Friedrich Karl Holtfreter (DE-US) showed that if embryonic amphibian cells from different tissues are dissociated then mixed together the cells re-associate into tissue specific masses—so called histotypic aggregates (1267-1269). This is an application to vertebrates of Wilson’s discovery with sponges. See, Wilson, 1907.

Sven Otto Hörstadius (SE) described the differences in the early development of regulative eggs (each blastomere can give rise to a whole embryo) and mosaic eggs (isolated blastomeres produce only fragments of an embryo, i.e., determinate cleavage). He discovered the existence of a double gradient of animalization and vegetalization in the echinoderm egg (1288, 1289).

Carey H. Bostian (US) and Phineas W. Whiting (US) worked out the mechanism for sex determination in the hymenopterean, Habrobracon. Homozygosity or hemizygosity at a particular multiply allelic locus produces a male while heterozygosity at this same locus produces a female (260, 2976, 2977). Whiting went on to show that nine different alleles are known for this locus (2978).

Schack August Steenberg Krogh (DK) found that the kidneys of whales and seals can produce urine with a salt concentration higher than seawater, thus they are able to drink seawater to replace the water lost from their tissues to the surrounding ocean (1527).

Emory Leon Ellis (US) and Max Ludwig Henning Delbrück (DE-US) demonstrated the one-step growth curve for phage. It showed that the progeny of the infecting phage particle appear only after a period of constant phage titer (815).

René Jules Dubos (FR-US) and Roland D. Hotchkiss (US) isolated the antibiotics tyrocidin and gramicidin from Bacillus brevis, a common soil bacterium. Tyrocidin is toxic to all living cells; gramicidin, which is active both in the test tube and in animals against gram-positive bacteria, is, however, limited to external use because it destroys erythrocytes. Gramicidin was the first antibiotic to be produced commercially and employed clinically. It is still in use today (743, 744, 746).

Walter John Dowson (GB) named the bacterial genus Xanthomonas, but it had been known as a group for some time and its characteristics described (731).

Hans Gaffron (DE) found that if certain unicellular green algae are deprived of oxygen, they cease to be capable of ordinary photosynthesis but become capable of reducing carbon dioxide in light if hydrogen is provided as a substitute reductant to replace water (986).

George Henry Hepting (US) identified the previously undescribed cause of wilt disease in mimosa as Fusarium. This was one of the first reports of tree disease caused by a fungal species in this taxonomic group (1216).

Carl G. Hartman (US), Chester Henry Heuser (US) and George Linius Streeter (US) followed macaque monkey embryonic development from the two-cell stage to the end of the embryonic period. Theirs is the first such complete description in a primate (1175, 1226).

Hugh G. Grady (US) and Harold L. Stewart (US) first identified the type 2 cell of the pulmonary alveolus as the cell of origin of the common alveologenic tumors of the lungs of mice (1063).

A Committee for the Standardization of Blood Pressure Readings defined diastolic and systolic pressures as: “The systolic pressure is the highest level at which successive sounds are heard…. The point where the loud clear sounds change abruptly to the dull and muffled sounds should be taken as the diastolic pressure. The American Committee recommend that if there is a difference between this point and the level at which the sounds disappear completely the latter reading should be regarded also as a measure of the diastolic pressure” (2204).

Norman Macdonnell Keith (US), Henry P. Wegener (US), and Nelson W. Barker (US) created four groups for hypertension, ranging from the benign group 1 to the so-called malignant hypertension as belonging to Group 4 (1422).

Robert Edward Gross (US) and John Perry Hubbard (US) were the first to carry out a successful ligation of a patent ductus arteriosus (a fetal blood vessel between the pulmonary artery and the aorta) (1092). The operation was performed on August 28, 1938. The patient made an uneventful recovery.

John C. Munro (US) had justified and described (but did not perform) an operation for ligation of the ductus arteriosus to repair patent ductus arteriosus (1947).

Glenn H. Algire (US), Harold W. Chalkley (US), Frances Y. Legallais (US), and Helen D. Park (US) postulated that the growth advantage of a tumor cell over its normal counterpart might not be due to "some hypothetical capacity for autonomous growth inherent within the [tumor] cell," but rather to its ability to continuously induce angiogenesis — that is, the formation of new blood vessels. They watched blood vessels migrate toward tumors in wound chambers. This was the first demonstration that tumors actively attract new blood vessels (30-32).

Isaac C. Michelson (GB) gave the first description of an angiogenic activity, regulated by oxygen, elaborated by the retina and mediating abnormal, retinopathic vessel growth (1890). Michelson's 'factor X' was eventually identified as vascular endothelial growth factor (VEGF) and confirmed to be the underlying causal factor of retinopathies.

Michael A. Gimbrone, Jr. (US), Stephen B. Leapman (US), Ramzi S. Cotran (US), and Moses Judah Folkman (US) reported that small balls of living tumor cells do not increase in size when suspended in the anterior chamber of the eye where they are deprived of vascularization. When such dormant balls of cells are moved from the anterior chamber to a nearby spot in the eye where they can attract vessels from the iris, they then grow exponentially. This is the first paper to provide direct evidence that the progressive growth of a tumor can indeed be absolutely dependent on angiogenesis (1032).

Douglas Hanahan (US) and Moses Judah Folkman (US) found that tumors appear to activate the angiogenic switch by changing the balance of angiogenesis inducers and countervailing inhibitors (1148).

Julian Sorell Huxley (GB) introduced the concept of the cline in evolutionary variation (1326). Cline is the gradual and continuous variation in genetic character over an extensive geographical area because of adjustments to changing conditions.

ca. 1940

It was established by general consensus that the vast majority of proteins are built up from a mixture of no more than 20 amino acids. From 1819 through 1936 only 20 amino acids had been found to be constituents of proteins based on isolation from protein hydrolysates.

1940

“Men think themselves free, because they are conscious of their volitions and of their desires and are oblivious to the causes which dispose them to desire and to will.” Charles Scott Sherrington (2474).

Samuel M. Ruben (US) and Martin David Kamen (CA-US) isolated carbon-14, which has a half-life of 5730 years. It quickly became one of the most useful of all isotopes in biochemical research and has also been turned to historical and archaeological use. Carbon-14 did not become widely available for metabolic studies until after World War II (1399).

Alfred Otto Carl Nier (US) published the description of a mass spectrometer for routine isotope abundance measurements and suggested that the apparatus was sufficiently accurate to measure the 13C/12C ratio if separated 13C was used as a tracer in biological investigations (1985).

Robert E. Eakin (US), Esmond Emerson Snell (US), Roger John Williams (US), and William A. McKinley (US) isolated from raw egg white a protein called injury-producing protein, which they named avidin (756-758). This protein forms a strong union with biotin (vitamin H) and prevents its absorption from the intestinal tract.

Moses Kunitz (RU-US) described the isolation of bovine ribonuclease in crystalline form (1545).

Leslie A. Epstein (US); Leslie A. (Epstein) Falk and Ernst Boris Chain (DE-GB) showed that lysozyme is an enzyme, that its substrate is peptidoglycan of bacterial cells, and that it hydrolyzes a beta-1, 4-glycosidic bond in the glycan backbone chain (845).

Edward Lawrie Tatum (US) and George Wells Beadle (US) isolated and crystallized what was called the v+ hormone from a bacterial culture supplied with tryptophan (2692).

Willard F. Verwey (US) was the first to describe staphylococcal protein A (SPA). He characterized it as a protein antigen present in type A staphylococci (coagulase-positive, alpha toxin positive, mannitol fermenting, and pathogenic; i.e., S. aureus) but not in the type B staphylococci (those lacking these characteristics) (2804).

Arne Forsgren (SE) and John Sjoquist (SE) showed that the well-recognized ability of all human sera to agglutinate S. aureus, which had been attributed to the universal presence of so-called natural antibodies, did not in fact represent an immune reaction. They showed that purified SPA bound to the Fc fragment of the immunoglobulin molecule, not to the antigen-binding Fab fragment (928). SPA became a valuable agent for immunochemistry and immunoassays.

Zacharias Dische (FR) discovered that the phosphorylation of glucose in erythrocytes is prevented by addition of phosphoglycerate. This may be the first example of end-product (negative feedback) inhibition (696).

Wilbur Paul Wiggert (US), Milton Silverman (US), Merton Franklin Utter (US), and Chester Hamlin Werkman (US) were the first to obtain soluble enzyme preparations capable of fermenting carbohydrates from bacteria (2986). This opened the way for bacteria to be used as experimental material in the study of metabolic pathways.

Merton Franklin Utter (US) and Chester Hamlin Werkman (US) demonstrated that bacteria have fermentative pathways involving many of the same reactions as yeast and muscle (2772, 2773).

Otto Gsell (CH) performed the first important trial of sulphatiazole (1095).

Donald Devereux Woods (GB) and Paul Gordon Fildes (GB) postulated that sulphanilamide acts by blocking the utilization of p-aminobenzoic acid by bacteria. This represents the origin of the essential metabolite inhibition hypothesis (3064-3066).

Andrew J. Krog (US), and Charles G. Marshall (US) used a swab technique to establish the bactericidal action of Zephiran, a quaternary ammonium compound, against bacteria commonly found on eating and drinking utensils. A one-minute exposure to a 1: 5,000 dilution was apparently sufficient to reduce bacteria surviving on tumblers to less than 100 per rim (1526).

Kenneth Bryan Raper (US), working at the Northern Regional Research Laboratory, isolated Penicillium chrysogenum strain NRRL 1951 from a moldy cantaloupe brought to him by a Peoria, Illinois housewife in 1943. This strain could produce large quantities of penicillin in submerged culture and subsequently became the parent of most all strains used in the production of penicillin. Once larger quantities of the antibiotic were available it was used to treat war casualties in Tunisia and Sicily in 1943.

Selman Abraham Waksman (RU-US) and Harold Boyd Woodruff (US) isolated the antibiotic actinomycin D from Streptomyces antibioticus. This antibiotic, the first ever isolated from actinomyces, is too toxic for use in animals (2857, 2858). Actinomycin D binds to DNA and blocks the movement of RNA polymerase (prevents RNA synthesis) in both prokaryotes and eukaryotes.

Gustav A. Kausche (DE) and Helmut Ruska (DE) took the first electron photomicrographs of chloroplasts (1413).

Linus Carl Pauling (US) proposed his version of the template mechanism for antibody synthesis. This introduced the concept of complementariness in association with biological macromolecules (2050).

Linus Carl Pauling (US) and Max Ludwig Henning Delbrück (DE-US) suggested that the surface of a gene somehow acts as a positive mold, or template, for the formation of a molecule of complementary (negative) shape (2053).

Karl Landsteiner (AT-US), Alexander Solomon Wiener (US), Philip Levine (RU-US) and Rufus E. Stetson (US) discovered that if a rabbit is injected with the blood of a rhesus monkey, (Macacus rhesus), its blood in turn develops an immune substance which will agglutinate not only the monkey’s blood but also that of about 85 percent of humans. Thus there must be in some human blood a substance which is also present in the monkey; for convenience they called it “Rh” (from rhesus) (1585, 1644).

Ronald Aylmer Fisher (GB) and Robert Russell Race (GB) postulated that the blood Rh factor is actually controlled by three pairs of closely linked genes leading to the possibility of 27 different Rh genotypes. They proposed a new nomenclature using the symbols C, c, D, d, E, e to designate the six antigens and anti-C, anti-c, anti-D, etc. to designate the antibodies specific for these antigens (Fisher's CDE hypothesis). In the 1944 paper Race also showed that in addition to the supposedly normal form of anti-Rh (anti-D) antibody, which agglutinated D-positive red cells directly, when they were suspended in a saline medium, there existed a variant, known as incomplete antibody (907, 2153). The D or Rh0 antigen is by far the most antigenic of all the Rh factors therefore anti-D antiserum is typically used in Rh blood typing.

Louis Klein Diamond (US) and Alexander Solomon Wiener (US) also discovered incomplete antibodies at about the same time (683, 2980).

Charles Richard Drew (US), medical supervisor of the "Blood for Britain Project," reported to the National Blood Transfusion Committee noting that for cases of shock, burns, and open wounds, plasma often worked better than whole blood. Plasma could also be stored and transported without refrigeration.

Øjvind Winge (DK) and Otto Laustsen (DK) showed that in the yeast Saccharomyces cerevisiae colonial characteristics, cell shape, and fermentative ability are under the control of genes that segregate during the reductive division (3031).

Charles Clemon Deam (US) produced his Flora of Indiana; a 1,236 page creation resulting from Deam personally collecting specimens in each and every one of the 1,016 townships in Indiana. This flora has excellent keys; Indiana distributional maps for all species and especially observational and/or critical notes about most. Deam's wife Stella faithfully worked along side her husband as a research assistant (631).

Kenneth C. Smithburn (US), Thomas P. Hughes (US), Alexander W. Burke (US), J.H. Paul (US), and Henry R. Jacobs (US) isolated the virus of West Nile Fever from the blood of an African native of Uganda (2543, 2544). In recent years WNV has spread beyond its traditional boundaries, causing illness in birds, horses, and humans in Europe and now the United States.

Friedrich Seidel (DE), Eberhard Bock (DE), and Gerhard Krause (DE), working with the golden-eyed fly, Chrysopa (Neuroptera) discovered the existence of a primary embryonic inductor in insects, which is associated with a specific germ layer, the ectoderm. Inductive stimuli originate in the ectoderm, and the underlying mesoderm responds with specific differentiations (2434, 2435). These were primarily Bock’s discoveries.

Soichi Fukuda (JP) discovered the prothoracic gland while studying the induction of pupation in the Chinese bivoltine race of silkworm (Bombyx) and the Japanese bivoltine race. This gland was found to be the source of internal secretion, which at a critical period releases into the blood a substance responsible for pupation (970-973).

John Henry Comstock (US) reported that the wing shape and vein pattern in insects is species-specific and is useful taxonomically (518).

Gavin Rylands de Beer (GB) refuted the theory that the embryonic development of an organism repeats the adult stages of the organism’s evolutionary ancestors (623).

Ruben A. Stirton (US) and George Gaylord Simpson (US) published phylogenetic studies of the North American horse. These are considered to be among the best and most complete phylogenetic studies ever written (2508, 2640).

Lewis Victor Heilbrunn (US) put forward the calcium ion release theory of muscle contraction in 1943, stating that calcium ion released from internal storage sites into the muscle cytoplasm by electrical or chemical stimuli, was assumed to activate the contractile material (1201).

Adalbert Farkas (IL) and Joseph Aman (IL) were the first to report resistance of a plant pathogen to an organic fungicide (861).

Thaddeus Robert Rudolph Mann (PL-GB) and David Keilin (PL-GB) determined that sulphanilamide is a potent inhibitor of carbonic anhydrase (1763).

William B. Schwartz (US) found that sulphanilamide produces an increased sodium, potassium and water excretion in patients with congestive heart failure; this likely results from inhibition of carbonic anhydrase in cells of the renal tubules (2425).

William Bloom (US), Margaret A. Bloom (US), Lincoln V. Domm (US), and Franklin C. McLean (US) were the first to demonstrate the importance of estrogens in laying down bone minerals in bone metabolism. They recorded the transformation of osteoblasts into osteoclasts (231-235).

Fuller Albright (US) and John D. Stewart (US) pointed out the role of steatorrhea in depleting the body of fat-soluble vitamins (27).

Erik Waaler (NO) described agglutination by rheumatoid sera of sheep cells sensitized with a sub-agglutinating coating of gamma globulin. This represents the discovery of the rheumatoid factor (RF). RF is an antibody directed to the Fc part of antibodies of the human IgG class. This and the description of the same phenomenon by Harry Melvin Rose (US), Charles Ragan (US), Elizabeth Pearce (US), and Miriam Olmstead Lipman (US) laid the foundation of one of the most important tests in rheumatology. Charles M. Plotz (US) and Jacques M. Singer (US) refined the test (2114, 2275, 2846).

Ralph Rossen (US), Herman Kabat (US), John P. Anderson (US), Lawrence M. Weinberger (US), Mary H. Gibbon (US), and John Heysham Gibbon, Jr. (US) determined that the cerebral cortex in humans is damaged irreversibly by relatively short periods of ischemia (a few minutes), while lower centers, such as the medulla, can survive for longer periods of temporary interruption in their supply of blood. They noted that a cessation of blood flow to the cerebral cortex for 6.8 seconds caused a loss of consciousness (2303, 2932).

Derek Ernest Denny-Brown (NZ-GB-US), W. Ritchie Russell (GB), Hugh John Forster Cairns (GB-US-GB), and Denis Williams (GB) did extensive research on cerebral concussion, post-concussion syndrome, closed head injury, disability from head injury, “shell-shock” and the effect on the head of high explosives (384, 652-657, 673-675, 3013).

Oscar V. Batson (US) found it possible to explain most cases of aberrant malignant metastases, aberrant pyogenic metastases and aberrant embolism following air injections by the demonstrated role of the vertebral vein system (136).

Robert Fiske Griggs (US) was perhaps the first to place plant rarity into an ecological context, acknowledging that plants do not statically interact with their surrounding environment. He also observed a geographic component to rare species distributions: some occur only in very restricted sites while others are more widespread, but sparsely populated. Griggs speculated the former were relics that had previously covered a larger area, but had become “slowly dying vestiges of races once widespread." In addition, he proposed that “habitat choice” or specificity was an ecological determinant of rare species occurrence and that certain types of habitats (e.g. rock outcrops, oceanic islands, and river margins) consistently harbored rare plant assemblages. The most resounding theory produced from this seminal paper was the notion that many plants are rare because they are poor competitors, predominantly existing in early successional or “ecologically young” environments where competitive pressures are low (1087).

Marcel Ravidat (FR), Jacques Marsal (FR), Georges Agnel (FR), and Simon Coencas (FR) discovered the cave at Lascaux, France where man produced representational art on the walls. It contains a great collection of Paleolithic art 10,000 to 15, 000 years old (2).

There occurred a widespread epidemic of rubella (German measles) in Australia.

1941

Albert Hewett Coons (US), Hugh J. Creech (US), R. Norman Jones (US), and Ernst Berliner (DE) attached fluorescent dyes to antibodies then used them to detect antigens; the so-called direct fluorescent antibody technique. The first fluorescent dye they used was B-anthryl isocyanate, which gives a blue fluorescence. Later they used fluorescein, to detect pneumococcal antigens. It gives a green fluorescence. This discovery made it possible to trace antigen and antibody within cells (537, 538).

Albert Hewett Coons (US) and Melvin H. Kaplan (US) improved the ability of the technique to localize antigens in tissue cells (539). This immunofluorescent technique is so important because it permits the detection of antibodies, antigens, and virtually any antigenic substance.

Archer John Porter Martin (GB) and Richard Laurence Millington Synge (GB) introduced liquid-liquid partition (column) chromatography which depends on the establishment of an equilibrium between two liquid phases (e.g., chloroform and water), one of which (water) is immobilized by being held by a solid support (e.g., silica gel), as the other (chloroform) flows through the column. Note: both high-pressure gas-liquid partition chromatography (GLC) and high-pressure liquid chromatography (HPLC) were first proposed in this paper (1784).

Fritz Prior (AT) and Erika Cremer (DE) developed gas chromatography (GC). Prior, in 1947, succeeded in separating oxygen and carbon dioxide on a charcoal column - a technical achievement for which he received his PhD (568, 2135).

Anthony T. James (GB) and Archer John Porter Martin (GB) developed high-pressure gas-liquid (partition) chromatography (GLC). They used the new column with great success to separate a variety of natural products (1352).

Douglas McClean (GB) found that some streptococci are capable of producing hyaluronidase (1815).

Francis Peyton Rous (US) and George W. Wilson (US) concluded from experimental studies on dogs that loss of blood volume, not loss of erythrocytes, was the important consideration in hemorrhage. Even after gross hemorrhage, these workers were able to restore the blood pressure to normal, and maintain it at the normal level, by replacing the blood they had removed with an equal quantity of plasma (2307).

Douglas B. Kendrick, Jr. (US) reported on the use of human albumin to treat traumatic shock. “. . .This patient was 20 years of age and was admitted to the hospital 16 hours after injury. He had a bilateral compound continued fracture of the tibia and fibula. He had fractures of five ribs with associated pleural damage, pneumothorax and subcutaneous emphysema. At the time of admission, his blood pressure was 76/30. Two bottles of albumin, consisting of approximately 25 grams, were injected over 30 minutes. The blood pressure after injection was 106/70 . . . his blood pressure remained above 130 . . . he has had no evidence of circulatory failure since the albumin was administered . . . this patient appeared quite groggy and irrational when I first saw him, but 12 hours later he was very clear mentally and appeared to be feeling better" (1432).

Isidor Schwaner Ravdin (US) reported on the effectively of using Cohn’s albumin to treat victims of the Pearl Harbor attack for burns and shock. Injected into the blood stream, albumin absorbs liquid from surrounding tissues, preventing blood vessels from collapsing; the finding associated with shock. "All seven patients were given albumin, and all showed prompt clinical improvement, including one whose state was so critical that the administration of albumin to him was debatable. There was no question as to his response: He was unconscious in the morning when he was given 250 grams of albumin. In the afternoon, he was talking, but was disoriented. The following morning, he was given the same amount of albumin. Twenty-four hours later, the edema had disappeared and he was taking food by mouth" (2200).

Paul Hermann Müller (CH) discovered that 1,1,1-trichloro-2, 2-bis (p-chlorophenyl) ethane or dichloro-diphenyl-trichloroethane (DDT) is a potent insecticide with low toxicity for higher organisms (1941-1944). This compound was originally synthesized in 1873 by Othmar Zeidler (Othmar Ziedler) (DE) for his Ph.D. thesis work. He knew nothing of its biological activity (3096).

Samuel B. Barker (US) and William H. Summerson (US) developed a colorimetric method for identifying lactic acid in biological materials. It is applicable to a wide variety of biological materials following deproteinization (127).

Ernst Klenk (DE) isolated a product from a cerebroside fraction and named it neuraminic acid (1459). The predominant form in mammalian cells being N-acetylneuraminic acid.

Cecil James Watson (US) and Samuel Schwartz (US) developed the Watson-Schwartz Test for the qualitative detection of porphobilinogen in urine. This test is to identify patients who carry the genetic trait for hepatic porphorias associated with neurologic lesions. It is a bedside urine test which can distinguish between cases of porphobilinogen (porphyria) and urobilinogen (pellagra) (2919).

Roger Adams (US) isolated and synthesized tetrahydrocannabinol and several of its analogues (8). Tetrahydrocannabinol is the active chemical in cannabis and is one of the oldest hallucinogenic drugs known.

Edward Lawrie Tatum (US) and Arie Jan Haagen-Smit (NL-US) identified the v+ vitamin of Drosophila as l-kynurenine (2693). Kynurenine is ubiquitous in insects, despite its extremely low concentration. It is in the metabolic pathway, which leads to the production of brown pigments (skotommins).

Yiquan Chen (AU) and Gilles J. Guillemin (AU) reported that the kynurenine pathway is an effective mechanism in modulating the immune response and in inducing immune tolerance. This is achieved by accelerating the degradation of tryptophan and the generation of kynurenines (449).

Hershel K. Mitchell (US), Esmond Emerson Snell (US), and Roger John Williams (US) isolated folic acid from spinach (folium = leaf (Lat.)) and named it. They showed it to be a growth factor for Streptococcus lactis R (S. faecalis) (1899). It is also called folate, pteroylglutamic acid, and vitamin B9, vitamin M.

Samuel M. Ruben (US), Merle Randall (US), Martin David Kamen (CA-US), and James Logan Hyde (US) used C18O2 and H218O containing 18O (heavy oxygen) to show that all oxygen liberated in photosynthesis originated in water; none came from carbon dioxide, and that the oxygen of CO2 enters into organic compounds (2318). Because 18O is not radioactive, Ruben used a mass spectrometer to find out where the oxygen from the water went.

Fritz Albert Lipmann (DE-US) presented the general hypothesis for energy transfer in living cells, to which Herman Moritz Kalckar (DK-US) also made important contributions. Lipmann postulated that ATP functions in a cyclic manner as a carrier of chemical energy from the degradation or catabolic reactions of metabolism, which yield chemical energy, to the various cellular processes that require an energy input. ATP is generated from ADP by coupled or linked phosphorylation reactions at the expense of energy yielded by degradation of fuel molecules. The ATP so generated is postulated to donate its terminal phosphate group to specific acceptor molecules, to energize them for carrying out various energy-requiring functions in the cell, e.g., the biosynthesis of cell macromolecules (chemical work), the active transport of inorganic ions and cell nutrients across membranes against gradients of concentration (osmotic work), and the contraction of muscles (mechanical work). As the energy of ATP is delivered to these energy-requiring processes, the ATP undergoes cleavage to ADP and inorganic phosphate. The ADP is then rephosphorylated at the expense of energy-yielding oxidation of fuels to yield ATP, thus completing the cellular cycle. The terminal phosphate group of the ATP was thus visualized as undergoing constant turnover, being continuously transferred to acceptor molecules and continuously replaced by phosphate groups that become energized during the catabolic degradation of cell fuels. He gave the energy-rich phosphate bond its name and invented the mark, ~, called the squiggle, as in —O~P— by which it is shown (1394, 1686).

Konrad Emil Bloch (US) and Rudolf Schoenheimer (DE-US) carried out isotope tracer studies which demonstrated that creatine is synthesized by the transfer of an amidine group from arginine to glycine, with the formation of guanidinoacetic acid which is then methylated to give creatine (228).

Carl Ferdinand Cori (CZ-US) and Gerty Theresa Cori, née Radnitz (CZ-US), Earl W. Sutherland (US), and Sidney P. Colowick (US) worked out the lactic acid metabolic cycle (Cori cycle) in which the breakdown of muscle glycogen, with formation of lactic acid, which enters the bloodstream, is converted to liver glycogen, which in turn breaks down and into glucose, which is carried to muscles where it is reconverted to muscle glycogen (542, 545, 548, 549, 2666).

Barry Commoner (US) and Kenneth Vivian Thimann (GB-US) found that concentrations of 10-5 M of iodoacetate could halt coleoptile growth but produce no effect on cellular respiration. They assumed that only a small fraction of respiration might be involved in growth (517).

Albert Imre Szent-Györgyi (HU-US), Ilona Banga (AT-HU), Tamas Erdös (HU), Mihály Gerendás (HU), Wilfred F.H.M. Mommaerts (US), and Ferenc Brunó Straub (HU), demonstrated that artificial fibrils made from myosin and another protein, which they named actin, contracted when ATP was added. The combination of actin with myosin was named actomyosin (119, 2676, 2679-2681).

Ferenc Brunó Straub (HU) and George Feuer (HU) reported that G-actin contains bound ATP and during polymerization of actin the ATP is hydrolyzed to bound ADP and Pi. Straub postulated that the transformation of G-actin-ATP to F-actin-ADP plays a role in muscle contraction (2654).

Hans Hermann Weber (DE) and Hildegard Portzehl (DE) prepared single muscle fibers from glycerol treated psoas muscles that developed tension equal to the intact muscle and reproduced the entire contraction-relaxation cycle of the muscle. Thus, it was proven without doubt that the interaction between actin, myosin and ATP is the basic mechanism for the contraction-relaxation cycle in skeletal muscle (2926).

Miyoshi Ikawa (US), Mark Arnold Stahmann (US), Karl Paul Gerhard Link (US), and Ivan Wolff (US) synthesized comparable compounds including warfarin (Coumadin). It is one of the drugs used today to treat deep vein thrombosis as well as to limit the danger of blood clots in patients with artificial valve replacements. Large doses are used in rat poison because it leads to uncontrollable internal bleeding (1331, 2604).

George Wells Beadle (US) and Edward Lawrie Tatum (US), who had previously collaborated in efforts to establish the chemical identity of substances I and II in the synthesis of Drosophila eye pigment, developed a new experimental approach for the study of the genetic control of metabolic reactions. They had become discouraged over the difficulties they encountered with Drosophila as an object for biochemical studies and turned their attention to a fungus, the bread mold Neurospora crassa. According to Beadle: “With the new organism our approach could be basically different. Through control of the constituents of the culture medium we could search for mutations in genes concerned with the synthesis of already known chemical substances of biological importance. We soon found ourselves with so many mutant strains unable to synthesize vitamins, amino acids and other essential components of protoplasm that we could not decide which ones to work on first.”

Genetic crosses between the Neurospora wild-type and the many mutants isolated and characterized in this manner revealed that most of them owe their growth factor requirement to the mutation of a single gene in the Neurospora genome. Furthermore, detailed biochemical study of the aberrant metabolism of the mutants showed that most of them carry a block at a single step in the reaction sequence leading up to the synthesis of the amino acid, vitamin, purine, or pyrimidine required for growth.

George Wells Beadle (US) and Edward Lawrie Tatum (US) proposed what Norman Harold Horowitz (US) would call the one-gene one-enzyme theory of gene action (1282). This proposal was based on their studies of mutants of the mold Neurospora crassa. The approaches they developed were extremely important not only for study of the gene-enzyme relationship but also for the analysis of the pathways of intermediary metabolism. Wild-type, i.e., unmutated, Neurospora can grow on a simple medium containing glucose as sole carbon source and only ammonia as nitrogen source. However, exposure of Neurospora spores to x-rays yields some mutant cells no longer capable of growing on this simple medium. Such mutant cells will grow normally if the medium is supplemented with the specific metabolite whose biosynthesis was impaired by the mutation. For example, some mutants of Neurospora are unable to grow unless the medium contains arginine, suggesting that an enzyme required in the synthesis of arginine from ammonia is genetically defective in these mutants. For lack of arginine such mutant cells cannot manufacture their proteins.

The mutant cells can utilize arginine for protein biosynthesis and show normal growth only when this amino acid is supplied in the medium. Further studies show that not all mutants of Neurospora defective in the capacity to make arginine are identical; they differ with respect to the specific step in the pathway of arginine biosynthesis that is genetically defective.

The one-gene-one-enzyme theory had nothing to say about how the gene actually manages to direct the formation of the enzyme under its dominion. Above all, it did not include the idea that the gene directs the assembly of amino acids into a polypeptide chain of given primary structure. Elucidation of the physical nature of the gene and of its role as the information element of the enzyme-cannot-make-enzyme paradox was to be the work of molecular genetics, the birth of which, it should be noted, was rendered valuable midwife service by the one-gene-one-enzyme theory (145, 146, 150).

Kenneth Mather (GB) coined the term polygene and describes polygenic traits in various organisms (1799).

Tracy Morton Sonneborn (US) explained the complex life cycle of Paramecium including macronuclear regeneration and cytoplasmic exchange and the finding that autogamy—the uniparental nuclear reorganization that periodically occurs in many paramecia—is sexual (2565, 2566).

William F. Diller (US) was the first to report autogamy in Paramecium aurelia (694).

Paul G. Smith (US), John Charles Walker (US), and William J. Hooker (US) proved for the first time that improper nutrition in plants is an important factor for initiation and eventual severity of vegetable diseases (2540, 2884-2887).

Ake Gustaffsson (SE) produced agriculturally superior new strains of cereals by selection from mutants produced by x-irradiation (1108, 1109).

George K. Hirst (US), Laurella McClelland (CA) and Ronald Hare (CA) discovered that influenza virus would spontaneously agglutinate chicken erythrocytes in saline. Antibodies to the virus will inhibit the agglutination. This became a direct means of recognizing the presence of this virus and measuring its titer in cell culture (1242, 1243, 1817). The reaction became known as the Hirst reaction.

Stuart Mudd (US) and Thomas Foxen Anderson (US) used the electron microscope to visualize the combination of antibodies with the flagellar and somatic antigens of bacteria (1928).

Dorsey W. Bruner (US) and Philip R. Edwards (US) demonstrated that Salmonella paratyphi A grown in media containing suppressive antisera of one sort can shift to one of four different antigenic phases (326).

Louis Gershenfeld (US), Vera Elaine Milanick (US), and David Perlstein (US) discovered that acidity decreases the antibacterial efficiency of many quaternary ammonium compounds so decidedly that they are completely ineffective at pH 3, and only weakly bactericidal at pH 4 (1010, 1011).

Zelma Baker (US), Robert W. Harrison (US), and Benjamin F. Miller (US) discovered that quaternary ammonium compounds are not very selective in their germicidal efficiency (109).

William Trager (US) was the first to grow the malarial parasite (Plasmodium) in vitro in a procedure which proved repeatable (2748, 2749).

John Holmes Dingle (US), Lewis Thomas (US), and Allan R. Morton (US) established the efficacy of sulfadiazine in the treatment of meningococcal meningitis (695).

Jacob Earl Thomas (US) developed a method for collection of bile under physiologic conditions by using a special cannula (2713).

Charles Brenton Huggins (CA-US), Clarence Vernard Hodges (US), and Roland E. Stevens (US) demonstrated the effects ofcastration, of estrogens, and of androgens on serum phosphataselevels in patients with extensive metastatic carcinoma of theprostate. They reported large clinical improvements in a significantnumber of these patients after orchiectomy and estrogen treatment. This was the first indication that a major type of cancer could be controlled by purely chemical means (1319, 1320).

Eric George L. Bywaters (GB) and Desmond Beall (GB) were the first to describe a syndrome found in many air raid casualties. The syndrome was observed in patients who were buried for several hours with pressure on a limb. They went into shock some time later, and then, despite fluid replacement, developed renal damage and died within a week (383).

Bernhard Zondek (DE-IL) reported that menstruation in women could be delayed (producing a limited amenorrhea) up to 70 days by the administration of estrogenic hormone. He realized that this had clinical significance (3109).

Frank W. Foote, Jr. (US) and Fred W. Stewart (US) initially diagnosed and described the related pattern of infiltrating lobular neoplastic breast disease in women. It is also referred to as lobular carcinomain situ (LCIS). This has been considered a special type of premalignancy ever since (924).

Robert Edward Gross (US) and William E. Ladd (US) wrote Abdominal Surgery of Infancy and Childhood, the first textbook on surgery in children (1561).

1942-1953

Polio continued to ravage the U.S., peaking in 1952 with about 60,000 cases (1482).

1942

“At that subtle moment when man glances backward over his life, Sisyphus returning toward the rock, in that slight pivoting he contemplates that series of unrelated actions which becomes his fate, created by him, combined under his memory’s eye and soon sealed by his death. Thus, convinced of the wholly human origin of all that is human, a blind man eager to see who knows that night has no end, he is still on the go. The rock is still rolling.

I leave Sisyphus at the foot of the mountain! One always finds one’s burden again. But Sisyphus teaches the higher fidelity that negates the gods and raises rocks. He too concludes that all is well. This universe henceforth without a master seems to him neither sterile nor fertile. Each atom of that stone, each mineral flake of that night-filled mountain, in itself forms a world. The struggle itself toward the heights is enough to fill a man’s heart. One might imagine Sisyphus happy.” Albert Camus (398).

“To think that physics or chemistry ought to be defined in terms of matter or physiology in terms of life is more than an egregious blunder; it is a threat to the existence of science. It implies that people know what matter is without studying physics or chemistry, and what life is without studying physiology.” Robin George Collingwood (508).

Harold H. Strain (US), Winston M. Manning (US) and Garrett Hardin (US) showed that chlorofucine, later known as chlorophyll c, is not an artifact (2649, 2650).

Jordi Folch (ES-US) showed that cephalin is not a single lipid but rather a mixture of at least three lipids (phosphatidyl ethanolamine, serine and inositol). Folch was the first to have elucidated the structure of phosphatidyl serine (917, 918).

Otto Fritz Meyerhof (DE-US) presented what has become known as the Embden-Meyerhof-Parnas pathway (1865).

Konrad Emil Bloch (US) and David Rittenberg (US) used isotope labeling techniques to show that acetate contributes in a major way to the synthesis of fatty acids, as well as, both the aliphatic side chain and to the tetracyclic moiety of sterol molecules (225-227, 2249).

Henry N. Little (US) and Konrad Emil Bloch (US) predicted that a two-carbon metabolite of acetate is the principal if not the sole building block of cholesterol (1690).

Dean Burk (US) found that the metabolism of the regenerating liver, which grows more rapidly than most tumors, is not cancer metabolism, but perfect aerobic embryonic metabolism (342).

Herman Moritz Kalckar (DK-US) and Sidney P. Colowick (US) discovered that muscle extracts of myokinase (adenylate kinase) catalyze the reaction ATP + AMP becomes 2ADP. This is a vital reaction because it returns AMP to ADP, which can be phosphorylated to ATP. The absence of adenylate kinase leads to phosphate accumulating as AMP (512, 1395).

Karl Landsteiner (AT-US) and Merrill Wallace Chase (US) announced that delayed hypersensitivity could be transferred with cells (444, 1580). Their findings resulted in a clear separation of the class of immune responses initiated by cells from those mediated by circulating immunoglobulins.

Amchem Corp. introduced 2,4-D as the first in a series of phenoxyacetic acid herbicides to control broadleaf weeds in corn (Zea mays), wheat (Triticum spp.), barley (Hordeum vulgare), sorgham, sugar cane (Saccharum officinarum), grass pastures, and in turf. ref

Samson R. Dutky (US) developed a way to produce spores of Bacillus popilliae to provide effective suppression of the Japanese beetle by inducing bacterial milky spore disease —the first commercial microbial pesticide (752).

Sheldon C. Reed (US), Carroll Milton Williams (US), and Leigh E. Chadwick (US) found that individual flies from various inbred strains of Drosophila can beat their wings at 12,000 to 14,000 beats per minute during sustained flight until exhaustion sets in after as much as three hours, or more than 2 million double wing beats (427, 2207).

Gordon Lynn Walls (US) wrote an important book on the eye of reptiles entitled, The Vertebrate Eye and Its Adaptive Radiation. He emphasized the profound differences between the eye of snakes and lizards, and suggested that snakes evolved from nocturnal lizards (2889).

Ernst Gutmann (CZ), Ludwig Guttmann (DE), Peter Brian Medawar (GB), and John Zachary Young (GB) damaged peripheral nerves of young and adult rabbits and dogs so that their axons would be severed, leading to degeneration of the distal part. They then followed the progress of regrowth from the cut stump over time. In most cases, no regeneration was seen for 3-7 days. Axons then appeared to grow at a constant rate of 3-5 mm per day. Surprisingly, however, functional recovery was not detectable for 2-3 weeks after the first axons had reached the end organ. Monitoring of functional recovery was one of the unique dimensions of this paper. Their clear demonstration that regeneration and functional recovery were very different served as a powerful impetus for further work (1111).

Frank Kingsley Sanders (GB) and John Zachary Young (GB) performed experiments suggesting that physical constrictions in the Schwann cell guides through which regeneration occurred were important determinants of the limitation of axon diameter. Knowing that these constrictions increased with time after denervation, they stressed the importance of performing nerve repair surgery as soon as possible following injury (2354).

Ernst Gutmann (CZ) and John Zachary Young (GB) showed that the Schwann cell guides critical for regeneration through the distal nerve also play critical roles in accurate reinnervation of muscle fibers (1112).

William Cumming Rose (US), Julius E. Johnson (US), William J. Haines (US), M. Jane Oesterling (US), Morton Shane (US), Madelyn Womack (US), Leonard C. Smith (US), Byron E. Leach (US), Minor J. Coon (US), Haines B. Lockhart (US), G. Frederick Lambert (US), Donald T. Warner (US), Aleck Borman (US), Robert L. Wixom (US), and Eugene E. Dekker (US) demonstrated that humans require eight amino acids in their diet (isoleucine, leucine, threonine, lysine, methionine, phenylalanine, tryptophan, and valine) as opposed to the ten required by rats and dogs. They noted that all essential amino acids must be supplied in the L-isomeric form with the exception of methionine, which can be used in either the D-, or the L- form. They even calculated the minimum daily requirement for each of these essential amino acids. Cystine was found to spare part of the methionine requirement and tyrosine spare part of the phenylalanine requirement. Glycine, glutamic acid, urea, and ammonium salts could all supply nitrogen necessary for synthesis of the non-essential amino acids (2277-2287, 2289-2295).

Jules Freund (AT-US) and Katherine McDermott (US) made a variation in oil adjuvants, which allowed them to be used with any antigen. They emulsified water in oil with the assistance of a water-miscible lanolin-like material to incorporate both dried inactivated tubercle bacilli and the target antigen in a single aggregate preparation. This was the original Freund’s complete adjuvant (949). This provided a method for inducing antibody formation and cellular responses to substances which are weakly antigenic.

Rudolf Schoenheimer (DE-US) and Hans T. Clarke (US) applied radioactive tracers to the study of the biosynthesis of cell structures and concluded that the body is in a state of dynamic equilibrium with the continual release and uptake of chemical substances to and from a metabolic pool (2400).

Charles H. Rammelkamp, Jr. (US) and Chester S. Keefer (US) developed a method for determining the concentration of penicillin in body fluids and exudates (2158). At this time penicillin was a rare and precious commodity.

George K. Hirst (US) used penicillin to thwart bacterial contamination during the isolation of influenza virus from unfiltered throat washings inoculated into the amniotic sac of the developing chick embryo (1243).

William Smith Tillett (US), Margaret J. Cambier (US), Harold Dunn (US), William H. Harris, Jr. (US), and James E. McCormack (US) studied penicillin therapy in cases of pneumococcal pneumonia and concluded that: 1) tissue levels of penicillin are more important than serum levels, 2) it is not the total daily dose of penicillin which results in recovery from the disease, but its duration of therapy, 3) during recovery the patient develops type-specific antibodies by the seventh to the tenth day after infection, and 4) if penicillin therapy is interrupted before the 7-10 day period following infection the patient will relapse and experience a recurrence of the disease (2716-2718, 2723, 2724). These results represent the first clear-cut demonstration of a seminal principle of antibiotic therapy, namely, that the antibiotic serves to limit the growth of the infectious agent until the appropriate immune responses of the host can be marshaled and result in its eradication.

Wilhelm Sigmund Feldberg (DE-GB) and Alfred Fessard (FR) made the first experimental demonstration of the electrogenic action of acetylcholine (864).

Harold R. Griffith (CA) and G. Enid Johnson (CA) were the first to produce muscular paralysis by the injection of a purified preparation of curare (intocostrin) as an adjuvant to surgical anesthesia. They used it to facilitate access to the abdomen during an appendectomy (1085).

Harry Fitch Klinefelter, Jr. (US), Edward Conrad Reifenstein, Jr. (US), and Fuller Albright (US) described a clinical syndrome characterized by gynecomastia, aspermatogenesis without A-Leydigism, and increased excretion of follicle-stimulating hormone. This condition would become known as Klinefelter’s syndrome. The majority of Klinefelter’s individuals have an extra female chromosome, resulting in a 47XXY karyotype. Other patterns of chromosomal aberration such as XXYY, and some mosaic patterns may result in the same syndrome. It is the most frequent type of intersexuality, occurring in one per 500-700 live male births (1463).

Clinton Nathan Woolsey (US) and Edward M. Walzl (US) selectively stimulated localized regions of auditory nerve fibers in the cochlea of the cat and mapped the patterns of evoked responses on the auditory cortex of the brain’s temporal lobe. This was the first demonstration of tonotopic (actually cochleotopic) organization of the auditory cortex (3082).

Clinton Nathan Woolsey (US) and D. Fairman (US) found a second tonal map ventral to the first with the sound spectrum in reverse order (3077).

Harlow W. Ades (US) found a secondary acoustic area in the posterior ectosylvian gyrus of the cat (9).

Werner Kuhn (CH) and Kaspar Ryffel (CH) hypothesized that the production of hypertonic urine by the kidney might result from a concentration mechanism by counter-current between descending and ascending limbs of Henle's loops (1542).

Heinrich Wirz (CH), Bartholomew Hargitay (CH), and Werner Kuhn (CH) proposed that the mammalian kidney concentrates urine by means of a counter-current mechanism. “These findings indicate that the concentration of the urine occurs without steep osmotic gradients. The loops of Henle are an example of a hairpin counter-current system. They prepare a hypertonic surrounding for the collecting ducts so that the contents of the collecting ducts are being concentrated by loosing water in this hypertonic milieu.” The tubular urine becomes osmotically concentrated in its descending limb, diluted in its ascending limb, and finally concentrated in the collecting ducts by the diffusion of water into the hyperosmotic medullary interstitium (1157, 3036-3038).

Carl W. Gottschalk (US) and Margaret Mylle (US) determined the hydrostatic pressure in renal tubules and small vessels of the rat kidney (1061).

Carl W. Gottschalk (US), Margaret Mylle (US), William E. Lassiter (US), Karl J. Ullrich (US), Bodil Schmidt-Nielsen (DK-US), Roberta O’Dell (US), and Gundula Pehling (US) used the micropuncture technique on various mammalian species with different kidney anatomies under three different conditions to show virtual equality of osmolarity in collecting ducts and at the bend of the thin loops of Henle during antidiuresis. These experiments provided definitive proof that urine is concentrated by countercurrent multiplication (1060, 1062, 2760).

William E. Lassiter (US), Carl W. Gottschalk (US), and Margaret Mylle (US) found a large net addition of urea to the fluid in the loop of Henle, indicative of urea recycling in the renal medulla (1602).

Heinrich Pette (DE) coined the word panencephalitis when he realized that some forms of viral encephalitis having a different name in different regions of the globe were in fact worldwide (2088).

Fuller Albright (US), Charles H. Burnett (US), Patricia H. Smith (US), and William Parson (US) described pseudohypoparathyroidism, a hypoparathyroidism in which there is evidence that the cause of the disturbance is the failure of the target organ(s) to respond to the hormone (24).

Harry Keil (US) was the first to propose that discoidal lupus erythematosus and systemic lupus erythematosus are forms of the same disease, and that they could even present transitional forms. It was also Keil who clearly outlined the differential diagnosis of cutaneous manifestations in order to distinguish between lupus erythematosus and dermatomyositis (1416).

Paul Klemperer (AT-US), Abou D. Pollack (US), and George Baehr (US) found that “the apparent heterogeneous involvement of various organs in disseminated lupus had no logic until it became apparent that the widespread lesions were identical in that they were mere local expressions of a morbid process affecting the entire collagenous tissue system…. A similar widespread alteration of collagen has also been noted in certain cases of diffuse scleroderma.” They defined the collagen diseases as chronic or acute processes, localized in connective tissue, especially in its intercellular components but with multiple locations throughout the organism. Due to this last phenomena they coined the phrase diffuse diseases of collagen (1456).

Arnold Rice Rich (US) and John E. Gregory (US) demonstrated that the lesions of periarteritis nodosa, rheumatic carditis, and pneumonitis, and some forms of glomerulonephritis are caused by the anaphylactic type of hypersensitivity (1083, 2228, 2230-2236).

Karl Theodore Dussik (AT) and Friederich Dussik (AT) are generally regarded as the first physicians to have employed ultrasound in medical diagnosis. They located brain tumors and the cerebral ventricles by measuring the transmission of ultrasound beam through the head, employing a transducer on either side (751).

George D. Ludwig (US) and Francis W. Struthers (US) were among the first to use pulse-echo ultrasound on animal tissues. They investigated the detection of gallstones using ultrasound, the stones being first embedded in the muscles of animals (1720).

John Silas Lundy (US) opened the first post-anesthesia recovery room in the world. Here patients were provided with specially trained personnel to monitor their recovery from the anesthetic agent (1725).

Charles Sutherland Elton (GB) was a community ecologist. He did important early studies on food webs. His speculations on interaction of population dynamics and selection foreshadowed the founder effect principle (819).

Ernst Walter Mayr (DE-GB-US) wrote Systematics and the Origin of Species from the Viewpoint of a Zoologist in which he gave systematics the first adequate integration of taxonomy, genetics, and natural history. Here he also produced the biological species concept, stating that species are “groups of actually or potentially interbreeding populations which are reproductively isolated from other such groups.” The 1942 paper contains the first statement of the founder principle (1806-1808). See, Aristotle, ca. 350 B.C.E. on species.

Raymond L. Lindeman (US), while studying the cycling of nutrients through a lake, realized that organisms are ecologically linked to their abiotic environment. The lake was an integrated system of the biotic and abiotic, to which he gave the name ecosystem. His trophic-dynamic viewpoint was an attempt to demonstrate how the day-to-day processes within a lake affected the long-term changes of ecological succession (1680).

Edward Smith Deevey, Jr. (US) described the biostratonomy of Linsley Pond in Connecticut. From his data he could read the 12,000-year history of the changes of conditions and communities within the pond, changes in the climate above it, and some of the activities of human population around it (638).

1943

Henrik Carl Peter Dam (DK) for his discovery of vitamin K and Edward Adelbert Doisy (US) for his discovery of the chemical nature and synthesis of vitamin K were awarded the Nobel Prize in physiology and medicine.

George Charles de Hevesy; Georg Charles von Hevesy (HU-DE-SE-DE) was awarded the Nobel Prize in Chemistry for introducing metabolic tracer methodology using radioactive lead and phosphorus.

Edward Joseph Conway (IE) determined that the oceans during the geological period when the original vertebrates evolved (Ordovician) had salinity very similar to the oceans of today (528). This is strong evidence against the blood-reflects-the-early-seas hypothesis.

Julius Hyman (US-GB) produced mono- and bis-adducts of hexachlorocyclopentadiene (hex) by reacting it with cyclopentadiene (2113).

Clyde W. Kearns (US), Lester Ingle (US), and Robert Lee Metcalf (US) tested these products and found that the mono-adduct’s (chlordene) insecticidal potency was about one-fourth that of dichloro-diphenyl-trichloro-ethane (DDT) or 2,2-di (4-chlorophenyl)-1,1,1-trichloroethane but that it was to volatile to be useful (1415).

Leslie James Burrage (GB) and James Crosby Smart (GB), in 1943, showed that it is the gamma isomer of benzene hexachloride that is insecticidal (368, 2521).SeeMichael Faraday, 1825 and Van der Linden, 1912.

Charles E. Clifton (US) reported that penicillin can be produced in good yield in continuous flow cultures, and that such a method is commercially feasible (488).

Britton Chance (US) deduced the mechanism of peroxidase action in great detail. His results strongly supported the theory that enzymes combine with their substrate forming a temporary enzyme-substrate complex (433).

Frederick W. Barnes, Jr. (US), Rudolf Schoenheimer (DE-US), Konrad Emil Bloch (US), Charles Tesar (US), and David Rittenberg (US) established that purine compounds of the tissues and the excreta are rapidly synthesized from simple metabolic units and not from preformed substances such as arginine, urea, and histidine (128, 224, 2700).

Barry Commoner (US), Seymour Fogel (US) and Walter H. Muller (US) demonstrated that auxin would promote water absorption against an osmotic gradient. The effect is inhibited by iodoacetate (516).

Alfred A. Harper (GB) and H.S. Raper (GB) discovered pancreozymin, a hormone released from the small intestine, which stimulates the secretion of pancreatic enzymes (1162).

Samuel M. Ruben (US) hypothesized that in photosynthesis the reduced pyridine nucleotide and the ATP needed to reverse the Embden-Meyerhof-Parnas pathway are generated by coupling to the light-dependent reduction of water (2314).

Michael Doudoroff (RU-US), Nathan Oram Kaplan (US), and William Zev Hassid (RU-GB-US) demonstrated that a glucosyl moiety of sucrose is transferred by enzyme to phosphorous. This was the first demonstration of such a sugar transfer. Glucose-1-phosphate and fructose were found to be the products of this sucrose breakdown by the bacterium Pseudomonassaccharophila. They found that this reaction was easily reversed leading to the synthesis of sucrose; the first such synthesis discovered (726).

Robert Emerson (US) and Charlton M. Lewis (US) determined that during photosynthesis in Chlorella quantum yields, as measured by oxygen release, are high when exposed to 400-440 and 560-580 nanometer ranges of light with a dip at about 490 nanometers (829).

Otto Fritz Meyerhof (DE-US) and Renate Junowicz-Kocholaty (US) re-determinedthe equilibrium constant for the isomerase and aldolase reactions inthe presence and absence of inorganic phosphate, cozymase, andWarburg's oxidizing enzyme. They found that their values agreedwith those previously determined and that equilibrium is notinfluenced by the presence of inorganic phosphate, cozymase,or Warburg's enzyme. They were also unable to detect the formationof any substance that would break down into glyceraldehyde phosphate andphosphate (1867).

Carl Ferdinand Cori (CZ-US) and Gerty Theresa Cori, née Radnitz (CZ-US), using liver tissue extract, presented evidence for the enzyme which forms the one to six glycosidic linkages in amylopectin (549).

David Nachmansohn (RU-DE-US), Richard Threlkeld Cox (US), Christopher W. Coates (US), and Adao L. Machado (BR) found that the production of very strong currents by electric eels is connected with the breakdown of phosphocreatine (1953).

David Nachmansohn (RU-DE-US) and Adao L. Machado (BR) proved that electric tissue containsenzymes capable of utilizing the energy of ATP for the acetylationof choline by choline acetylase (1954). This was the first time ATPhad been shown to drive a synthetic reaction other than phosphorylation.

Albert Lester Lehninger (US) showed that ATP is required for the oxidation of fatty acids and gave evidence that the fatty acid is enzymatically activated at the carboxyl group. He also found that fatty acids are oxidized to yield two-carbon units that can enter the tricarboxylic acid cycle (1621).

Alfred Ezra Mirsky (US) and Arthur Wagg Pollister (US) demonstrated that histones are common to all somatic nuclei (1898).

Salvador Edward Luria (IT-US) Max Ludwig Henning Delbrück (DE-US), and Thomas Foxen Anderson (US) were the first to see bacterial ribosomes. They did not, at the time, know what they were (1729).

Salvador Edward Luria (IT-US) and Max Ludwig Henning Delbrück (DE-US) published a paper entitled Mutations of Bacteria from Virus Sensitivity to Virus Resistance. This paper represents the birth of bacterial genetics. With their paper, Luria and Delbrück did for bacterial genetics what Mendel had done for general genetics—namely, to show for the first time what kind of experimental arrangements, what kind of data treatment, and, above all, what kind of sophistication are required for obtaining meaningful and unambiguous results (1728).

Bacteriophages (phages) are subcellular parasites that infect, multiply within, and kill bacteria. The T1 (T one) phage active on Escherichia coli—with which Luria and Delbrück were working— has a head and a tail and occupies about one-thousandth the volume of its Escherichia coli host. It is too small to be seen with a light microscope. Upon collision of such a T1 phage particle with an Escherichia coli cell, the particle is fixed to the cell surface by interaction with a T1-phage receptor site; such sites form part of the Escherichia coli cell wall. The interaction of a phage particle with its phage receptor site has the same high degree of specificity as the interaction of the active site of an enzyme with its substrate. Once fixed to the receptor site, the T1 phage particle invades the Escherichia coli cell and destroys it. Imagine an experiment in which about 105Escherichia coli cells are spread on the surface of a nutrient agar plate containing 1010 T1 phage particles. Upon incubation of that plate, the agar surface will most likely remain completely blank: not a single Escherichia coli colony can be expected to appear on that plate, since every bacterium of the inoculum will be infected, and hence killed, by one or more of the 1010 phage particles on the plate.

The point of departure of Luria and Delbrück’s paper was the observation that, upon spreading about109, rather than only about 105, Escherichia coli cells upon agar containing an excess of T1 phage particles, the chances are rather good that a few Escherichia coli colonies will appear on the agar surface. If one of these few surviving colonies is picked, and a sample of the cells making up the colony replated on agar containing T1 phage, it will be found that all of these cells grow into colonies. That is to say, all of the bacteria in one of the few surviving colonies are T1-resistant or Tonr. By convention of genetic nomenclature, Ton designates the infectious agent and the superscripts r or s designate resistance or sensitivity of the host. The T1 resistant bacteria retain their Tonr character upon further cultivation in the absence of any T1 phage, as can be demonstrated by spreading samples of the Tonr culture growing in the T1-free medium on T1-containing agar. Thus the Tonr bacteria perpetuate and pass on to their descendants the property of resistance to the phage, in contrast to the T1 sensitivity passed on by the normal TonsEscherichia coli cells. The physiological basis of the T1 resistance resides in the structure of the bacterial cell wall, in that the cell wall of Tonr bacteria does not feature the T1 receptor sites, to which the phage particles attach before they infect and kill the Tonscell. Hence the T1 phage particles cannot attach to, and, therefore, cannot kill the Tonr cells. Since the few Tonr cells isolated by plating the original Escherichia coli culture on the T1-containing agar have clearly descended from the Tons ancestors that make up the bulk of the population, they must represent stable variants of the normal Tons type. That is, an element of the bacterium that controls the synthesis of the T1 receptor sites in the cell wall of the normal Tons cell has changed in some way in the Tonr variant so that these receptor sites are no longer formed.

Such instances of the appearance of stable bacterial variants resistant to one or another antibacterial agent had been well known to bacteriologists for many years when Luria and Delbrück designed an experiment that was to enable them to decide between the following two fundamentally different views of the origin of stable Tonr variants in cultures on TonsEscherichia coli: 1) the Tonr character is induced as a consequence of the exposure of the Tons bacterial culture to T1 phage, 2) the Tonr character pre-exists in a few cells before exposure of the bacterial culture to T1 phage (1728). This great experiment is often referred to as the fluctuation test. It gave proof that mutations are usually not induced by the environment.

Luria and Delbrück’s statistical proof of the spontaneous nature of bacterial mutation and measurement of mutation rate represents not only the beginning of bacterial genetics, but also the first of several fortunate choices of experimental material that were to aid the further development of this field. Their finding of spontaneous mutation to phage resistance turns out to have depended on their use of the T1 phage, a phage that is a virulent bacteriophage. Had they happened to have picked one of the phage types that came to be known as temperate bacteriophages, they would have had to conclude (wrongly) that the bacterial variants acquire their resistant character by contact with the antibacterial agent (1728).

J. Bruce Hamilton (GB) clearly showed from clinical and laboratory observations that keratitis can be due to the herpes simplex virus (1137). Keratitis has multiple causes, one of which is an infection of a present or previous herpes simplex virus secondary to an upper respiratory infection, involving cold sores.

Bacterial infection of the cornea can follow from an injury or from wearing contact lenses. The bacteria involved are Staphylococcus aureus and for contact lens wearers, Pseudomonas aeruginosa.Pseudomonas aeruginosa contains enzymes that can digest the cornea.

Ragnar Granit (FI-SE) proposed a physiological theory of color perception. “The mechanism of color reception is organized by the peripheral visual apparatus, the number of color-sensitive elements is relatively limited, and these elements represent widely different regions of the visible spectrum (1066).” He also made the first ganglion cell recordings from a mammalian retina, the cat retina (1067).

Paul R. Dumke (US), Carl Frederic Schmidt (US), and Harry H. Pennes (US) made the first quantitative measurements of the cerebral blood flow in lightly anesthetized macaque monkeys and determined cerebral oxygen consumption in the same state and under deeper anesthesia as well as convulsive activity (750, 2390).

Seymour Solomon Kety (US) and Schmidt described a quantitative method for measuring cerebral blood flow in humans using nitrous oxide (Kety-Schmidt technique) (1435, 1436, 2389). The method is based upon the uptake by the brain of the diffusible nitrous oxide supplied by way of the arterial blood. These works led directly or indirectly to the development of current methods for the measurement of regional blood flow, metabolism, and the visualization of functional activity throughout the human brain.

H. Nakamura (JP) and H. Tsumagari (JP) were the first to describe the tobacco stunt disease (1965).

Victor Assad Najjar (LB-US) and L. Emmett Holt, Jr. (US) discovered that bacteria in the bowl of man are synthesizing thiamine (vitamin B1) which is being absorbed into the blood stream (1963).

Robert Edward Hungate (US) described an anaerobic cellulose digesting bacterium from the rumen of cattle (1324).

Frank Baker (GB), S.T. Harris (GB), R.M. Pearson (GB), and J.A.B. Smith (GB) used histochemical and histophysical methods to identify cellulose cleaving microorganisms in the rumen of cattle and sheep, and in the caeca of the horse, guinea pig, rabbit, and hen. They observed that each host species tends to harbor a characteristic microbiota (107, 108, 2059-2061).

Wilson Smith (GB) and J.H. Hale (GB) determined that pathogenic strains of Staphylococcus aureus and also of the albus variety regularly produce coagulase while nonpathogenic strains do not (2541).

Tracy Morton Sonneborn (US) showed that various cases of non-Mendelian inheritance could be classified into distinct groups, most involving interactions between nuclear genes and the cytoplasm (2567, 2568).

Maxwell E. Power (US) began his very important contribution to insect neuroanatomy by studying the distribution of nerve tracts and specific fibers in the brain of Drosophila as well as its thoracico-abdominal nervous system (2127-2129).

Carroll Milton Williams (US), and Muriel Voter Williams (US) demonstrated the neuromuscular network in the thorax that controls the wing-beat in Drosophila (3012).

Wilton R. Earle (US), Emma Shelton (US), Edward L. Schilling (US), Thomas H. Stark (US), Nancy P. Straus (US), Mary F. Brown (US), and Anderson Nettleslip (US) were the first to establish a permanent mammalian cell line in vitro. The cells were originally derived from an explant of subcutaneous tissue from the C3H strain of mice and after many subculturings designated the L strain. They found they could alter the morphology and growth characteristics of these cells by treatment with a carcinogen. When these altered cells were injected into healthy mice, tumors were produced. Earle and Nettleship (US) noted that all of these normal cells maintained in vitro, even those not treated with a carcinogen, eventually became malignant and reverted (transformed) to a more primitive morphology (759-763, 1974, 2463).

Paul Bruce Beeson (US) published the classic description of transfusion-transmitted hepatitis. He linked the occurrence of jaundice in seven cases to blood or plasma transfusions the patients had received a few months prior, providing the quintessential description of transfusion-transmitted hepatitis (161).

Clinton Nathan Woolsey (US) discovered a second somatic sensory receiving area in the cortex of the cat, dog, and monkey (3076).

Edgar Douglas Adrian (GB) independently made the same discovery at a slightly later time in the Shetland pony (13).

Min Chueh Chang (CN-US) discovered that applying ice to the scrotum of sheep causes severe disintegration of sperm from the lower end of the epididymis. He referred to this as cold shock (436).

Edward David Korn (US) found that the “clearing factor” is,in fact, a heparin-activated lipoprotein lipase that occursin and is released by heparin from heart and adipose tissues. It hydrolyzes the triacylglycerols of lipoproteins but notsimple oil emulsions; the latter could, however, be convertedto substrate by complexing with a high-density lipoprotein (1491-1493).

Jan Gosta Waldenström (SE) described three patients with an elevated erythrocyte sedimentation rate (ESR) who had hyperproteinemia and petechiae of their lower extremities without evidence of malignancy (2877). Although he coined the term purpura hyperglobulinaemica, this entity is now recognized as benign hypergammaglobulinemic purpura of Waldenström (BHPW).

James Purdon Martin (GB) and Julia Bell (GB) were the first to describe the fragile X syndrome (Martin-Bell syndrome) (1787).

Herbert A. Lubs (US) reported the fragile site on the X chromosome (1714).

John Freeman Loutit (GB) and Patrick Loudon Mollison (GB) devised a disodium-citrate-glucose mixture as a blood preservative, which made possible the storage of whole blood for up to three weeks (1712).

Robert Edward Gross (US) and Charles A. Hufnagel (US) performed the successful corrective surgery of coarctation of the aorta. In infants this narrowing of the aorta is typically proximal to its junction with the ductus arteriosus. The adult type is at or distal to the junction. This condition is usually fatal (1090, 1091, 1093).

David Lambert Lack (GB) wrote The Galapagos Finches (Geospizinae) a Study in Variation; Darwin’s Finches; The Life of the Robin; and Swifts in a Tower, all important contributions to ornithology and an introduction of competition theory into animal ecology, stressing the importance of ecological isolation in speciation, and providing a cogent model for adaptive radiation (1556-1559).

1944

“From Type III pneumococcus a biologically active fraction has been isolated…which in exceedingly minute amounts is capable…of inducing the transformation of unencapsulated R variants of Pneumococcus Type II into fully encapsulated cells of the same specific type as that of the heat-killed microorganisms from which the inducing material was recovered…. The active fraction…consists principally…of a highly polymerized, viscous form of desoxyribonucleic acid.” Oswald Theodore Avery (90).

Joseph Erlanger (US) and Herbert Spencer Gasser (US) shared the Nobel Prize in Physiology or Medicine for their determination of how different nerve fibers (cells) conducted their impulses at different rates. All else being equal, the velocity of the impulse varies directly with the thickness of fiber.

Raphael Consden (GB), Arthur Hugh Gordon (GB), and Archer John Porter Martin (GB) developed the technique of paper chromatography and stated that, “the separation depends on the differences in partition coefficient between the mobile phase and the water-saturated cellulose, instead of differences in adsorption by the cellulose” (526).

Albert Schatz (US), Elizabeth Bugie (US), and Selman Abraham Waksman (RU-US) isolated a new antibacterial substance they designated streptomycin. It was isolated from two strains of an actinomycetes related to an organism described as Actinomyces griseus (2380, 2855). It was first used on humans May 12, 1945. Waksman is credited with coining the word antibiotic (against life) (2853). See, Papacostas, 1928. Streptomycin prevents the transition from initiation complex to chain elongating ribosome and also causes miscoding in prokaryotes only.

Oswald Theodore Avery (CA-US), Colin Munro MacLeod (US), and MacLyn McCarty (US) discovered that genetic information is contained in, and transmitted by DNA (90). Avery was 67 years old when this paper appeared. It is a mystery to many that he was never awarded the Nobel Prize. Erwin Chargaff (AT-US) commented, “the ever rarer instance of an old man making a great scientific discovery. It had not been his first. He was a quiet man; and it would have honored the world more, had it honored him more” (441).

Eugene F. Jansen (US), and Doris J. Hirschmann (US) discovered the antibiotic subtilin, produced by Bacillus subtilis. It was later shown by others to be antagonistic chiefly to gram-positive bacteria. It also inhibits Mycobacterium spp. and a number of pathogenic higher fungi (1358).

Reginald Ernest Balch (GB-CA) and Frederick Theodore Bird (CA) provided one of the first reports on the use of a virus to control an arthropod pest, i.e., the European spruce sawfly (110).

Charles H. Gray (US), Edward Lawrie Tatum (US), Raymond R. Roepke (US), Raymond L. Libby (US), and Margaret H. Small (US) described bacterial mutants in Escherichia coli which they characterized as auxotrophs, from the Greek aux-, increase (not from the Latin auxi-, help), and trophe, food. The normal or wild-type cells he called prototrophs, from protos, first, or minimal.

In order to isolate rare bacterial mutants that have a nutritional requirement for their growth with which the parent Escherichia coli can dispense, they followed essentially the same procedure that had yielded the Neurospora mutants in 1940. For this procedure large numbers of Escherichia coli cells were plated on nutrient agar—that is, on complete medium. The colonies, which appeared after overnight incubation on the complete medium, were then picked, and part of each bacterial clone was tested to ascertain whether it would grow on a minimal medium—that is, agar containing a synthetic medium deficient in all components except the minimum necessary to grow the prototroph. In this way Gray and Tatum found that, whereas the overwhelming majority of colonies consisted of bacterial clones capable of growing on both media, about 1% of the colonies that grew on the complete medium were made up of bacteria that were unable to grow on the minimal medium. That is, these rare colonies were made up of clones of nutritional Escherichia coli mutants, which require for their growth some factor present in the complete medium but absent from the minimal medium.

The exact nature of the growth requirement of any particular auxotrophic mutant strain could be established by placing samples of the auxotrophic bacterial clone into a series of minimal media to which various putative growth factors, such as amino acids, vitamins, purines, and pyrimidines, had been added. The growth requirement is then inferred to be that substance whose addition to the minimal medium is necessary and sufficient to allow growth of the auxotroph.

Gray and Tatum established that many of their Escherichia coli auxotrophs responded to the addition of just one single factor to the minimal medium. (By convention the auxotrophic mutants are designated with a minus sign and a three letter abbreviation for the specific synthetic deficiency, e.g., Thr -, Pro -,Trp -. The prototrophic condition carries a plus sign , e.g., Thr +, Pro +, Trp +. It is noted that the minus or plus superscripts affixed to these symbols mean inability or ability to synthesize the substances represented by the three-letter abbreviation, and not, as with sugar-fermentation mutants, inability or ability to utilize the substance as a source of carbon and energy) (1071, 2272).

Victor Assad Najjar (LB-US), George A. Johns (US), George C. Medairy (US), Gertrude Fleischmann (US), and L. Emmett Holt, Jr. (US) discovered that bacteria in the large intestine of man are synthesizing riboflavin (vitamin B2) which is being absorbed into the blood stream (1964).

Lothar Szidat (CL) found eggs of the fish tapeworm, Diphyllobothrium latum, in the intestines of two human bodies preserved in a peat bog in East Prussia since the early glacial period, i.e., Weichselian at 10- 110 Ka (2683).

J. Zed Young (GB), Paul Alfred Weiss (AT-US), and Helen B. Hiscoe (US) discovered that axoplasm of neurons is continuously flowing down nerve fibers at the rate of 0.2 mm per day (2936, 3089).

William Hugh Feldman (US) and Horton Corwin Hinshaw (US) were the first to demonstrate successful in vivo treatment of tuberculosis with streptomycin (867, 1240).

Peter Brian Medawar (GB), Leslie Brent (GB), Rupert Everett Billingham (GB-US), and Elizabeth M. Sparrow (GB) established the immunological basis of the allograft reaction including an explanation of the second-stage phenomenon, i.e., an animal which has been grafted with foreign skin from the same donor on two successive occasions will reject the second graft more rapidly than the first (290, 1837-1840).

Peter Brian Medawar (GB) observed that presensitization of a recipient with leucocytes from the graft donor accelerated skin graft rejection, whereas erythrocytes had no effect. He therefore concluded that the search for histocompatibility antigens (coined in 1948) should be focused on the white cells, not the red cells, of the blood (1839).

William Christopher Stadie (US), Benjamin C. Riggs (US), and Niels Haugaard (US) wrote a series of papers on the oxygen poisoning of enzymes and tissues at hyperbaric pressures (2588-2596).

Aristides Azevedo Pacheco Leão (BR), while studying the epileptiform after discharge response of the cerebral cortex to electric stimulation in rabbits, discovered the spreading depression reaction—a response of the dorsolateral neocortex to electric or mechanical stimuli applied to its surface. This visible aura frequently precedes migraine headaches (1607-1609).

John Friend Mahoney (US), Richard C. Arnold (US), Burton L. Sterner (US), Ad Harris (US), Margaret R. Zwally (US) described the use of penicillin to treat syphilis (1756). One long-term result of this discovery was the virtual elimination of tertiary syphilis of the brain, once a leading cause of insanity throughout the world.

Arnold Rice Rich (US) clarified the pathogenesis of the spread of the tubercle bacilli in the body (2229).

James Gray (GB) in his studies of the mechanics of the tetrapod skeleton points out among other things that, in locomotion, limbs can function either as struts, providing force along their long axis, or as levers, providing a moment of force to supply torque around the attachment point (1075).

Roger Wolcott Sperry (US) severed optic axons in adult and immature anurans then noted that they reconnected to the optic tectum (the principal visual center) and visual function eventually returned, indicating that reflex relations in the brain had been correctly restored. To test how the restored vision had come about, regeneration was combined with a perturbation of the visual field produced by rotation of the eye. Control animals that had undergone regeneration of the optic nerve without rotation of the eye always showed correct responses when tested. Incorrect responses by those in which the eye had been rotated could not be attributed to any inherent defect in the regeneration process itself, and they could not be corrected by any functional process such as learning, even if they were of a maladaptive nature. Sperry inferred from these experiments that “the ingrowing optic fibers must possess specific properties of some sort by which they are differentially distinguished in the [brain] according to their respective retinal origins” (2576).

Roger Wolcott Sperry (US) created various experimental environments in test subjects: 1) excising the optic chiasma and rerouting the optic nerves (which are usually completely crossed in the amphibians that he used) to connect each eye to the ipsilateral lobe of the optic tectum, 2) transplant one eye to the opposite side, thus reversing its dorsal-ventral orientation without changing its nasal-temporal orientation, or vice versa. In these animals, the visuomotor responses were altered from normal in the direction that would have been predicted from their eye orientations. Histological studies showed a disorderly progression of the optic axons along the nerve, with almost all of them crossing to the contralateral tectum and only a scattering selecting the route to the side to which they would originally have connected. Thus it was evident that the regenerating axons were not passively following their old trajectories, and hence their final orderly reconnection to the optic tectum must have been determined by an intrinsic property reflecting the specific location of their cell bodies in the retina. Sperry inferred that the specific local properties would have been produced originally in the embryo “through a field differentiation of the retina” (2577).

John Rock (US) and Miriam Menkin (US) announced the first successful human in vitro fertilization (IVF) experiment (2270).

Grantly Dick-Read (GB) developed the concept of natural childbirth: that by elimination of fear and tension, labor pain could be minimized and anesthetics, which can be hazardous to both mother and child, rendered unnecessary (685).

David H. Rosenberg (US) and Philip A. Arling (US) were the first to successfully treat meningitis with intravenous and intrathecal penicillin (2297). Since then, penicillin has remained the drug of choice for the treatment of meningococcal meningitis.

Paul Jackson Kramer (US) and John P. Decker (US) determined that the eventual transformation of pine forests to hardwood forests results from the inability of pine seedlings to grow in the low light intensities under deciduous trees (1499). This work is one of the first explanations of the succession of plant species in natural communities.

1945

Artturi Ilmari Virtanen (FI) was awarded the Nobel Prize in Chemistry for his research and inventions in agricultural and nutrition chemistry, especially for his fodder preservation method.

Alexander Fleming (GB), Ernst Boris Chain (DE-GB), and Howard Walter Florey (AU-GB) were awarded the Nobel Prize for physiology and medicine for the discovery of penicillin and its curative effect in various infectious diseases.

Erwin Schrödinger (AT) wrote his little book What is Life ?, which had a profound effect on physical scientists. Since many of these physical scientists were suffering from a general professional malaise in the immediate post-war period, they were eager to direct their efforts toward a new frontier, which according to Schrödinger, was ready for some exciting developments. He tantalized physicists by suggesting that while the study of the gene would not elude the laws of physics, as established up to that date, it was likely to involve other laws of physics hitherto unknown. Their knowledge of biology was generally confined to stale botanical and zoological lore, and having one of the founding fathers of the new physics put the question, what is life? Provided for them an authoritative confrontation with a fundamental problem worthy of their mettle. Schrödinger’s book became a kind of catalyst of the revolution in biology that, when the dust had cleared, left molecular biology as its legacy. It is in this book that Schrödinger proposes the existence of an aperiodic solid polymer with potential as a miniature code containing information which is transmitted from one generation to the next (2422).

Robley Cook Williams (US) working with the electron microscopist Ralph Walter Greystone Wyckoff (US) developed the technique of metal shadow casting. This allows tiny objects to take on a three dimensional quality when viewed through the electron microscope (3015).

Gordon R. Baldock (GB) and William Grey Walter (GB-US) developed automated spectral analysis of EEG traces. A standard method for EEG analysis since its discovery has been to measure the power in various frequency bands, including alpha and delta, also beta (15-30 Hz), and theta (3-7 Hz). Walter used his skills in analog electronics to build a device that displayed the frequency content in an EEG trace, even as the trace was displayed with an ink-writing oscillograph, a pen whose fluctuations left a trace on moving paper that became the mainstay of electroencephalographers (111, 112).

James C. Gentles (GB) reported the successful treatment of dermatophytosis in guinea pigs with griseofulvin (1008). It was introduced for clinical use in 1959.

Alastair Campbell Frazer (GB) and Herbert G. Sammons (GB) demonstrated that the formation of mono- and diglycerides from triglycerides results from the action of pancreatic lipase (pancreatic triacylglycerol lipase) both in vitro and in vivo, with no free glycerol appearing during the first five hours of the reaction (940).

Linus Carl Pauling (US) speculated that the biological action of a protein is related to the shape of the surface into which the polypeptide folds (2051).

Erwin Brand (US), Leo J. Saidel (US), William H. Goldwater (US), Beatrice Kaseel (US), and Francis J. Ryan (US) reported the first complete amino acid analysis of a protein by chemical and microbiological methods. The protein was beta-lactoglobulin (277).Beta-lactoglobulin is the major whey protein in the milk of ruminants and some non-ruminants.

Frederick Sanger (GB), Hans Tuppy (GB), Edward Owen Paul Thompson (GB), Andrew P. Ryle (GB), Leslie F. Smith (GB), Ruth Kitai (GB), and Henry Brown (GB) developed a method for determining the nature and amount of the amino-terminal amino acid residues in a protein by using dinitrofluorobenzene. When they applied this methodology to insulin they concluded that each 12,000 molecular weight unit contained two amino-terminal glycine residues and two amino-terminal phenylalanine residues. Sanger postulated that, “The presence of four alpha amino groups suggests that the submolecule is built up of four open polypeptide chains bound together by cross-linkages, presumably chiefly disulfide linkages. It is, of course, possible that other chains may be present in the form of a ring structure with no free amino groups”. They later found that insulin was likely to be composed of two polypeptide chains, succeeding in determining the exact amino acid sequences for both chains of bovine insulin. This was the first demonstration that proteins contain a precise amino acid sequence (313, 2337, 2356-2363).

Donald Frederick Steiner (US), Ronald E. Chance (US), Robert M. Ellis (US), William W. Bromer (US), Ole Hallund (DK), Arthur Harold Rubenstein (US), Sooja Cho (US), Claudia Bayliss (US), Jeffrey L. Clark (US), Chris Nolan (US), Emanuel Margoliash (IL), Bradley Aten (US), Philip E. Oyer (US), James D. Peterson (US), and Franco Melani (US) found that insulin is synthesized first in the islet cells as a single-chained precursor, proinsulin. In the pancreatic duct proinsulin is subsequently converted to the two-chained form by the enzymatic removal of a segment from its middle after the formation of the three disulfide bonds (434, 1846, 1991, 2618-2621). This represents the first evidence for the existence of a novel family of endoproteolytic processing enzymes called proprotein convertases. See Roebroek, 1986.

Walter C. Schneider (US) described methodology by which DNA, RNA, and cellular protein can be separated from one another (2397, 2398).

Fritz Albert Lipmann (DE-US) discovered how pyruvate is oxidized to the intermediate formation of a reactive two-carbon fragment (active acetate) by studying a model system. He showed that pigeon-liver extracts, in the presence of added ATP, also affected the acetylation of the amino group of the drug sulfanilamide with acetate as the source of potential active acetate. He found that this reaction required—in addition to thiamine pyrophosphate—the presence of a heat-stable dialyzable factor, which he named cofactor coenzyme A (A for acetylation) (1687).

Feodor Felix Konrad Lynen (DE), Ernestine Reichert (DE), and Luistraud Kröplin-Rueff (DE) established the precise chemical mechanism by which coenzyme A carries acyl groups. They isolated an active form of acetate from yeast and showed it to consist of a thioester of acetic acid with the thiol or sulfhydral group of coenzyme A. The function of coenzyme A is to serve as a carrier of acyl groups in enzymatic reactions involved in fatty acid oxidation, fatty acid synthesis, pyruvate oxidation, and biological acetylations (1736-1738).

James Baddiley (GB), Eric M. Thain (), G. David Novelli (US), and Fritz Albert Lipmann (DE-US) worked out the structure of coenzyme A (95).

Horace Albert Barker (US) and Earl Reece Stadtman (US) found that coenzyme A participates in the metabolism of fatty acids (126).

Roscoe O. Brady (US) and Earl Reece Stadtman (US) detected three distinctly different thioltransacetylases in pigeon liver extracts; namely, thioltransacetylase A which catalyzes the transfer of the acetyl group of acetyl-CoA to reduced lipoic acid, 2-mercaptoethanol, and to a lesser extent to some other mercaptans, thioltransacetylase B which catalyzes the acetylation of 2-mercaptoethanol and 2-mercaptoethylamine, and a hydrogen sulfide thioltransacetylase that catalyzes the acetylation of hydrogen sulfide with the formation of thioacetic acid (275).

John Gilbert Moffatt (US) and Har Gobind Khorana (IN-US) synthesized coenzyme A (1901). NAD and lipoic acid were found to be requirements for coenzyme A activity.See, Lester J. Reed.

Herman Moritz Kalckar (DK-US) and Manya Shafran (US) discovered that phosphorolytic cleavage of nucleosides is similar to that of glycogen, e.g. ribose-hypoxanthine + Pi is converted to ribose-1-P + hypoxanthine. The equilibrium of this reaction lies to the left. This was the first demonstration of enzymatic synthesis of a nucleoside (1396, 1398).

Winston H. Price (US), Carl Ferdinand Cori (CZ-US), and Sidney P. Colowick (US) demonstrated that hexokinase activity is promoted by insulin but checked by another hormone in extracts from the anterior lobe of the pituitary gland, i.e., the hypophysis (2134). This first demonstration of a regulatory effect of hormone on enzyme opened a whole new field of investigation.

David Shemin (US) and David Rittenberg (US) observed that if 15N-labelled glycine molecules are given to human subjects it leads to hemin (ferriprotoporphyrin) molecules in which all four nitrogens are 15N. Serendipitously they found that the data allowed them to calculate the average life span of a human erythrocyte at 127 days (2466-2468).

Roland G. Westall (GB), Gerry H. Cookson (GB) and Claude Rimington (NO) found that a patient suffering from acute intermittent porphyria was excreting a monopyrrole (porphobilinogen). Porphobilinogen was postulated to be a "pyrrolic intermediate" in the synthesis of a group of organic pigments, which includes hemoglobin and chlorophyll (530, 531, 2952).

Samuel I. Beale (US), Simon P. Gough (US), and S. Granick (US) discovered the C5 pathway in which the first pyrrole ring of the four pyrrole rings in chlorophyll can be made by an alternative route for the synthesis of 5-aminolevulinate which starts from glutamate (in contrast to the synthesis from glycine and succinyl-CoA) (152).

Gunnar Östergren (SE) formulated the concept of selfish DNA. Speaking of non-coding B chromosomes, he stated that: “I think reasonable support may be given to the view that in many cases these chromosomes have no useful function at all to the species carrying them, but they often lead an exclusively parasitic existence” (2015).

Norman Harold Horowitz (US) and Jerry S. Hubbard (US) postulated how complex sequential metabolic pathways may have arisen as the result of selective pressure, i.e., the retrograde model.

Suppose that a contemporary cellular pathway makes a required substance such as an amino acid through the sequence A to B to C to D to E, in which A is a simple inorganic substance and E is the final organic product. Initially E was plentiful in the environment and was absorbed directly by primitive aggregates. Later, as E became scarce because of use, chemical selection favored pre-cells that could make E from D, a slightly less complex organic substance still found in abundance in the environment. As D became exhausted, selection favored assemblies that developed the pathway C to D, in which the even simpler substance C could be absorbed and used as raw material to make D. This process continued until the entire synthetic pathway, based on an essentially inexhaustible inorganic substance, was established (1281, 1283).

Milislav L. Demerec (Yugoslavian -US) and Ugo Fano (US) collected the group of seven bacteriophages later to be called the T-set. Their host is E. coli strain B. They were numbered consecutively as they were collected (most likely from sewage or feces) (646, 1378). Of the seven, the so-called T-even strains (T2, T4, andT6), which are similar structurally, antigenically, and genetically,proved the most useful for biochemical and genetic studies.

Alan Lloyd Hodgkin (GB) and Andrew Fielding Huxley (GB) were able to measure the resting and action potentials in single nerve fibers (cells) (1250).

Keith Roberts Porter (US), Albert Claude (BE-US), and Ernest F. Fullam (US) produced the first electron micrograph of an intact eukaryotic cell. The cell was a cultured fibroblast originating from a chick embryo, which was grown by Porter on polyvinyl film, then peeled off and transferred to a wire specimen grid. The cell was fixed with osmium tetroxide, washed and then dried in order to prevent evaporation in the electron microscope's vacuum chamber. Magnified 1600 times, this first electron micrograph of a cell reveals mitochondria, the Golgi apparatus and a lace-like reticulum which Porter later named the endoplasmic reticulum. The electron microscope used for this historic image was an RCA EMB model, operated by Fullam at the Interchemical Corporation in New York City (2122).

George Emil Palade (RO-US), Keith Roberts Porter (US), Frances Kallman (US) and Fritiof Stig Sjöstrand (SE) developed methods for fixation and thin sectioning that enabled many intracellular structures to be seen for the first time (2029, 2030, 2123, 2510).

Keith Roberts Porter (US) and Joseph Blum (US) developed the ultramicrotome. The invention took place in 1952 (2121).

Fritiof Stig Sjostrand (SE), Leonard G. Worley (US), Ernest Fischbein (US), and Jennie E. Shapiro (US) discovered the ciliary rootlet as an anatomical structure (2511, 3083). The cross-linking between the rootletsand other cytoskeletal elements indicate its important role as an anchorand support structure for the cilia.

Hermann Joseph Muller, Jr. (US) made an exceptionally farsighted interpretation of Oswald Theodore Avery’s work on the transformation of pneumococci (90). Muller stated, “There were, in effect, still viable bacterial ‘chromosomes’ or parts of chromosomes floating free in the medium used. These might, in my opinion, have penetrated the capsuleless bacteria and in part at least have taken root there.

A method appears to be provided whereby the gene constitution of these forms can be analyzed, much as in the crossbreeding tests on the higher organisms. However, unlike what has so far been possible in higher organisms, viable chromosome threads could also be obtained from these lower forms for in vitro observation, chemical analysis, and determination of the genetic effects of treatment” (1939). Note: Given as a Pilgrim's Trust Lecture before the Royal Society of London 1 November 1945.

Max Ludwig Henning Delbrück (DE-US) organized the first annual summer phage course at Cold Spring Harbor, New York. This course persuaded many young scientists to adopt phage as a tool for solving problems of a biological nature, especially the problem of defining a gene and its relationship to DNA.

Salvador Edward Luria (IT-US) discovered that bacteriophages could sport host-range mutants. These host-range mutants are able to overcome the resistance of phage-resistant mutant bacteria because the structure of the attachment organs of the mutant phage differs in some subtle way from that of the wild-type phage (1726).

Alfred Day Hershey (US) reported the isolation of r (rapid lysis) and h (host-range) phage mutants. This along with Luria’s work demonstrated to existence of various mutant forms (1223).

Max Ludwig Henning Delbrück (DE-US) developed a technique permitting the assay of the relative proportion of h and hplus types in a single plating of a bacteriophage suspension. h is a mutant T2 phage that can infect and grow on cells normally resistant to the T2 phage. The wild-type T2 phage is h plus which is capable of infecting normal cells but not Tto resistant cells. Ref

Edward B. Lewis (US) designated that in genetics there are two different types of position effects, S-type (stable) and V-type (variegated) (1648).

Balbina A. Johnson (US), Herbert Anker (US) and Frank L. Meleney (US) first described the antibiotic bacitracin, which they isolated from Bacillus licheniformis. It was found to be to toxic for internal use (1363).

Barbara McClintock (US) determined that the chromosomes of Neurospora and their behavior in the ascus are typically eukaryotic. She outlined the details of meiosis and described the seven chromosomes, noting that despite their small size they are individually recognizable by their distinctive morphology at pachytene. Pachytene pairing in a translocation heterozygote with the ascus types resulting from different modes of segregation when the translocation was heterozygous were described (1820).

Donald Frederick Poulson (US) studied embryonic development in Drosophila melanogaster by using deficiencies involving the entire X chromosome or reasonably large portions thereof. The results of one such deficiency, known as Notch-8, were detailed. “The most striking feature of such eggs is that they contain very little or no endoderm or mesoderm... the process of germ layer formation has been interfered with seriously... The ectoderm proliferates especially along the ventral mid-line and produces what appears to be a semblance of the early nervous system” (2125).

Donald Frederick Poulson (US) clearly demonstrated that the closely coordinated yet separate developmental steps involved in Drosophila embryogenesis are under the control of specific genes (2126).

Christopher Q. Doe (US) and Corey S. Goodman (US) studying the neural ectoderm of grasshoppers suggested a mechanism that we now know as lateral inhibition. Using laser micro beams to ablate one or more ectodermal cells in a group, they found that neuroblasts are specified by cell interactions. Initially, each undifferentiated cell within a sheet of neural ectodermal cells has an equal chance of becoming a neuroblast, but only one cell within a group takes on this role. Interactions between the cells of a group allow this one cell to enlarge into the neuroblast, which somehow prevents its neighboring cells from taking on the same identity; these cells instead become support cells or die (711).

Kristi A. Wharton (US), Kristen M. Johansen (US), Tian Xu (US) and Spyros Artavanis-Tsakonas (US) presented the primary structure of the major embryonic Notch transcript, which shows homology to the epidermal growth factor (EGF) and other proteins containing EGF-like repeats. Hydropathy plots suggest that the putative Notch protein may span the membrane. They relate these findings to the developmental action of Notch and speculate that the locus may be involved in a cell-cell interaction mechanism that is essential for the differentiation of the ectoderm into neural and epidermal precursors (2958).

Mikhail Petrovich Chumakov (RU), in 1944, was the first to identify and establish the viral etiology of the disease the Soviets called Crimean Hemorrhagic Fever. He passed the virus through human volunteers but was unable to isolate it (462).

David I. H. Simpson (IE), E.M. Knight (), Ghislaine Courtois (BE), Miles C. Williams (GB), M. Paul Weinbren (ZA), and John W. Kibukamusoke (AU) isolated and named Congo virus from several Congolese and Ugandan patients exhibiting a severe febrile illness (2505). The virus was eventually named Crimean-Congo hemorrhagic fever virus (CCHF), a member of the genus Nairovirus, family Bunyaviridae.

Jordi Casals (ES-US) found the Crimean virus indistinguishable from Congo virus, which was isolated in 1956 from a febrile child in Stanleyville (now Kisangani, Democratic Republic of the Congo), leading to the current designation, CCHF virus (406). CCHF produces high mortalities, up to 60%, and has been found in over 30 countries.

Kenneth Bryan Raper (US) and Charles Thom (US) wrote their monograph, Manual of the Aspergilli (2195).

Georgiana B. Deevey (US) and Edward Smith Deevey, Jr. (US) wrote a paper on the hematology of the black widow spider. This paper was the first to use life table analysis in the study of an arachnid (640).

Charles H. Rammelkamp, Jr. (US), with the Commission on Acute Respiratory Diseases and the New York State Department of Health, helped determine the relationship between epidemics of acute bacterial pneumonia and influenza (1193). This is the basis for the influenza surveillance by the Centers for Disease Control, which follows pneumonia prevalence as a surrogate for influenza.

Robert Royston Amos Coombs (GB), Arthur Ernest Mourant (GB), and Robert Russell Race (GB) found that erythrocytes which had been sensitized with incomplete anti-Rh antibodies and then washed free of unbound human globulin could be agglutinated by an anti-human globulin serum prepared by immunizing a rabbit with human gamma globulin or whole human serum (534, 535). Erythrocytes sensitized by nonagglutinating incomplete anti-Rh antibodies will agglutinate when mixed with anti-globulin antibodies, i.e., the DirectCoombs Test. Suspected cases of erythroblastosis fetalis may be tested in this manner.

Ray David Owen (US) was the first to apply the term tolerance to an immunological phenomenon. He used it to describe results in his studies on binovular twin cattle sharing a common placenta (freemartin cattle). Owen noted that “erythrocyte precursors from each twin fetus had become established in the other and had conferred on their new host a tolerance towards … foreign cells that lasted a lifetime.” These twins of different sex were in fact red-cell chimeras or genetic mosaics (2017, 2018).

Michael Francis Addison Woodruff (GB) and Bernard Lennox (GB) confirmed the freemartin concept in man when they found a pair of twins, one male the other female, who shared elements of different red cell types. Postulating a shared placental circulation between the two, they cross skin grafted them successfully (3063).

Robert Franklin Pitts (US) and Robert S. Alexander (US) showed that the hydrogen ion secreted by the renal tubules is responsible for acidifying the urine of mammals (2112).

Robert Franklin Pitts (US), William D. Lotspeich (US), Martha Barrett (US), and Ilse Langer (US) defined the properties of renal bicarbonate transport by examining the relationship between bicarbonate reabsorption and excretion at varying plasma bicarbonate levels. A renal threshold for bicarbonate excretion was defined at 24mM. They established the kidney’s ability to generate significant transepithelial carbon dioxide gradients, which were explained by a lack of effective carbonic anhydrase activity in the lumen of distal nephron segments. They noted a relationship between bicarbonate transport and excretion of acid, based on the observation that during acidosis the excretion of titratable acid varied inversely with the amount of bicarbonate administered (2108).

George H. Chambers (US), Eleanor V. Melville (US), Ruth S. Hare (US), and Kendrick Hare (US) found that in conscious dogs the secretion of the antidiuretic hormone (vasopressin) depends on the osmotic pressure of the blood plasma (432).

George Washington Corner (US), Carl G. Hartman (US), and George W. Bartelmez (US) described the development, organization, and breakdown of the corpus luteum in the rhesus monkey (Macacus rhesus) (554).

George Gaylord Simpson (US) placed all apes in one family, the Pongidae and all members of the genus Homo, extinct and extant, in a separate family, the Hominidae (2507).

Gordon R. Baldock (GB) and William Grey Walter (GB-US) developed automated spectral analysis of EEG traces. A standard method for EEG analysis since its discovery has been to measure the power in various frequency bands, including alpha and delta, also beta (15-30 Hz), and theta (3-7 Hz). Walter used his skills in analog electronics to build a device that displayed the frequency content in an EEG trace, even as the trace was displayed with an ink-writing oscillograph, a pen whose fluctuations left a trace on moving paper that became the mainstay of electroencephalographers (111, 112).

Anthonie van Harreveld (US) produced experimental evidence that after removal of part of the innervation of a muscle, the remaining motor units grow by adopting muscle fibers, which originally belonged to the dennervated motor units (2779).

Clinton Nathan Woolsey (US), John L. Hampson (US), and C.R. Harrison (US) mapped the somatic sensory projections to the cerebellar cortex and the organization of projections from the cerebral cortex to the cerebellar cortex in the cat and dog (1147, 3078).

Cecil James Watson (US), Samuel Schwartz (US), Violet Hawkinson (US), Moisés Grinstein (US), and Robert A. Aldrich (US) revealed that in most cases of porphyria the excreted porphyrins are derived from the liver, suggesting a defect in heme synthesis within this organ (1088, 2920).

Alfred Blalock (US), Helen Brooke Taussig (US), and Vivien Theodore Thomas (US) perfected what became known as the blue baby operation (Blalock-Taussig shunt)—subclavian artery attached to the pulmonary artery— to correct a defect of the large artery that supplies blood to the lungs. This defect allows so little blood to be pumped through the narrow passage that the oxygen intake is painfully curtailed.Blalock performed the operation on a human for the first time in 1946. Prior to this Vivien Theodore Thomas had performed this operation many times on dogs. Dr. Blalock, in collaboration with Dr. Taussig, developed procedures for the correction of a number of congenital heart lesions or anomalies of the great vessels of the heart, leading to morbus ciruleus, among them patent ductus arteriosis, tetrology of Fallot (blue baby syndrome), tricuspic atresia, and coarctation of the aorta (220, 2201).

Robert Edward Gross (US), in 1945, reported the first successful case of surgical relief for tracheal obstruction from a vascular ring (1089).

Paul H. Leslie (GB) showed how one simple mathematical technique can be used to make all the important demographic projections and how this technique can be applied to basic life table data of the sort that a laboratory or field ecologist usually obtains (1631).

1946

“Adapt or perish, now as ever, is Nature’s inexorable imperative.” Herbert George Wells (2944).

“Essential to a great discoverer in any field of nature would seem an intuitive flair for raising the right question…to ask something which the time is not yet ripe to answer is of little avail.” Charles Scott Sherrington (2475).

James Batcheller Sumner (US) for his discovery that enzymes can be crystallized and John Howard Northrop (US) and Wendell Meredith Stanley (US) for their preparation of enzymes and virus proteins in a pure form were awarded the Nobel Prize in Chemistry.

Hermann Joseph Muller, Jr. (US) was awarded the Nobel Prize in Physiology or Medicine for the discovery of the production of mutations by means of x-ray irradiation.

Edward Mills Purcell (US), Henry C. Torrey (US), Robert V. Pound (US), Felix Bloch (CH-US), William Webster Hansen (US), and Martin Packard (US) found that when certain nuclei were placed in a magnetic field they absorbed energy in the radiofrequency range of the electromagnetic spectrum, and re-emitted this energy when the nuclei transferred to their original state. This is nuclear magnetic resonant absorption (NMR) (222, 223, 2142, 2143).

Richard R. Ernst (CH) and Hans Primas (CH) designed and built advanced electronic equipment for improved nuclear magnetic resonance (NMR) spectrometers. In parallel, they developed the theoretical background for the optimum performance of the instruments (846).

Albert Claude (BE-US) developed differential centrifugation for isolating and purifying cell parts. He and others would use this technique to separate ribosomes, mitochondria, lysosomes, peroxisomes, and the Golgi complex into distinct fractions. This paper contains the first full explanation of the fractionation of mammalian cells by differential centrifugation (477).

George Hall Hogeboom (US), Walter Carl Schneider (US), and George Emil Palade (RO-US) significantly improved this methodology by carrying out the centrifugation in a concentrated solution of sucrose. This technique was considered to have made the method of isolating mitochondria complete (1257).

Erwin Brand (US) proposed that the first three letters in the name of an amino acid be used as an abbreviation for that acid, there being a few exceptions (276).

George Hall Hogeboom (US), Albert Claude (BE-US), and Rollin Douglas Hotchkiss (US) showed that the site of intracellular respiration is the mitochondrion (1256).

George Emil Palade (RO-US) produced the first electron photomicrographs of mitochondria, which revealed their cristae and outer membrane. He postulated that their structure was related to the function of such enzymes as succinic acid dehydrogenase and cytochrome c oxidase. These photomicrographs revealed that the enzymes of respiration reside within the inner membrane of the mitochondrion (2029).

Setsuro Ebashi (JP), Fumiko Ebashi (JP), Ayako Kodama (JP), Makato Endo (JP), Iwao Ohtsuki (JP) and Takeyuki Wakabayashi (JP) isolated troponin (native tropomyosin) and found that when skeletal muscle is stimulated by depolarization of the muscle membrane the level of calcium ions in the muscle increases and this increases the amount of calcium ions bound to troponin. The sensitivity of calcium ion binding to calcium ion concentration, together with the observation that at low calcium ion levels the actin-myosin interaction is inhibited but that this inhibition is reversed at higher calcium ion levels, clearly indicated that regulation of actin-myosin activity must relate to the binding of calcium ions by troponin (765-768, 771, 772).

Jörgen Lehmann (SE) discovered the anti-tubercular agent para-aminosalicylic acid (PAS) (1620). This drug when used along with streptomycin—discovered by Waksman—provided the first effective treatment of tuberculosis.

John C. Sonne (US), I. Lin (US), and John Machlin Buchanan (US), demonstrated that two nitrogen atoms are derived from the amide nitrogen of glutamine and that aspartic acid (or glutamic acid) contributes one nitrogen to the synthesis of the purine ring (2559, 2560).

Solomon Spiegelman (US) and Martin D. Kamen (US) suggested that copies of the information encoded within DNA are transmitted into the cell’s cytoplasm for protein synthesis (2578, 2579). This had great significance for future research into messenger RNA.

Maclyn McCarty (US) isolated, purified, and described for the first time the existence and properties of bovine pancreatic deoxyribonuclease (1812).

Carroll Milton Williams (US) began a series of experiments with the silkworm, Hyalophra (Platysamia) cecropia, which led to discoveries that at low temperatures the pupal brain becomes competent to secrete hormone. At high temperatures, which typically follow low temperatures in the seasons, specialized cells in the competent brain secrete a hormone, which reacts with the prothoracic glands causing them to secrete a growth, and differentiation hormone. This growth and differentiation hormone reacts with the pupal tissues to terminate diapause thus leading to development of an adult.

He also found that a brain hormone produced by larvae early in the spinning process promotes the secretion of the prothoracic gland growth and differentiation hormone which promotes pupation (3003-3011).

Philip Rodney White (US) was the first to attempt the production of a defined medium for the culturing of eukaryotic cells. The cells survived but did not multiply (2971, 2972).

Max Rubin (US) and Herbert R. Bird (US) discovered that an acid precipitate of a water extract of dried cow manure stimulates the growth of chicks. This would later be known as vitamin B12 (2320-2322).

Robert K. Callow (GB) and Philip Montagu d’Arcy Hart (GB) isolated the antibiotic licheniform from Bacillus licheniformis Weigmann emend. Gibson. It is especially effective against species of myxobacteria (390).

Edgar S. McFadden (US) and Ernest Robert Sears (US) discovered that the amphiploid between Triticum turgidum (wheat) and Aegilops squarrosa (goat-grass) is phenotypically very close to Triticum spelta (wheat). This confirmed earlier inference from hybrids involving Aegilops cylindrica (goat-grass) that the seven pairs of chromosomes (genome) in hexaploid but absent in tetraploid wheat had been derived from Aegilops squarrosa (goat-grass) (1823).

Milton R.J. Salton (US) demonstrated that the substrate for the lysis of Micrococcus lysodeikticus by lysozyme is the cell wall (2351).

Claes Weibull (US) observed that cells of Bacillus megaterium are transformed into wall-less, fragile, protoplasts when treated with lysozyme (2931).

Jean-Marie Ghuysen (BE) recounted how the molecular structure of bacterial cell walls was elucidated through a series of experiments utilizing various bacteriolytic enzymes, which attack specific molecular structures (1613).

Mary Lynne Perille Collins (US) and Milton R.J. Salton (US) were among the first to utilize detergents to solubilize bacterial membrane proteins (509).

Joshua Lederberg (US) and Edward Lawrie Tatum (US) demonstrated sexual recombination in Escherichia coli strain K-12. This recombination behavior strongly suggested that bacteria, like higher organisms, contain genes. Up to this point in time no bacterium of any sort had been shown to have genes. Lederberg was to name this phenomenon conjugation (1612, 1614, 2694).

Max Ludwig Henning Delbrück (DE-US), Alfred Day Hershey (US), Raquel Rotman (US), and William T. Bailey, Jr. (US) presented evidence suggesting that when bacteria are simultaneously infected by two different varieties of bacteriophage the burst of daughter phage shows characteristics derived from both parents, as though phage genes have recombined inside the host bacterium. This represents the discovery of genetic recombination in bacteriophage and the birth of phage genetics (644, 1223, 1224).

Kenneth M. Smith (GB) reported that two distinct viruses, tobacco vein distorting and tobacco mottle, when co-infecting tobacco (Nicotiana tabacum) plants, caused the tobacco rosette disease. This is considered the discovery of the first luteovirus-associated aphid-transmitted virus complex (2535, 2536).

Kenneth C. Smithburn (US), Alexander John Haddow (GB), and Alexander Francis Mahaffy (CA) isolated the Bunyamwera (BUN) virus from Aedes mosquitoes in 1943 at the Enteebe East Africa Research Institute in Uganda. It would become the type virus for the Bunyaviridae family (2542).

Jacques Lucien Monod (FR) and Alice Audureau (FR) demonstrated that Escherichia coli mutabile possesses the genetic information to produce the enzymes which allow utilization of lactose, whether lactose is present or not (1908).

Edward Lawrie Tatum (US) was the first to intentionally produce mutations in bacteria. He exposed Acetobacter and Escherichia coli to x-rays (2691).

Carl Clarence Lindegren (US) and Gertrude Lindegren (US) discovered that haplophase cultures of Sacharomyces cerevisiae contain two mating types which they designated a and alpha (1679).

Marcus Morton Rhoades (US) discovered the nuclear gene, iojap, a mutator gene that affects plastids. This is one of the first known cases of nuclear-cytoplasmic interaction. These alterations are heritable via the cytoplasm (2222).

Harold H. McKinney (US) was the first to report that oat mosaic disease has a viral etiology (1824).

M.T. Dyar (US) and Erling J. Ordal (US) found that bacteria die rapidly when the negative charge on their surface is neutralized by the positive charge on a quaternary ammonium compound. This suggests a relationship between surface charge and disinfecting power (755).

Ernest Aubrey Ball (US) excised Nasturtium and Tropaeolum shoot tips and grew them in a test tube. He excised the shoot tips with scalpels made of razor blade corners spot-welded onto sewing needles, which could be inserted into wooden holders. He also regenerated plantations of lupin (Lupinus) by culturing their shoot tips with leaf primordia (113, 114).

George Henry Hepting (US) found that pines inoculated with pitch canker fungus produced oleoresin flow with desirable results (1217).

Otto Rahn (DE-US) showed that agents, which adsorb them, diminish the germicidal efficiency of quaternary ammonium compounds (quats). Examples are, filter paper, charcoal, bentonite, and agar. He further showed that fatty surfaces cause quats to orient themselves in a specific direction as they are adsorbed. The hydrophobic end of the molecule is directed toward the fatty material while the germicidal N—OH group faces the aqueous phase (2157).

Robert A. Quisno (US) and Milton J. Foter (US) reported that an increase in temperature increases the germicidal efficiency of quaternary ammonium compounds, the temperature coefficient between 20°C and 37°C, being less than 2. They also reported that somewhat larger doses are required to kill gram-negative enterobacteria than streptococci and staphylococci, but rarely more than double the amount. A striking exception is Pseudomonas aeruginosa for which ten to twenty times as much is needed as for staphylococci. Mycobacterium spp. are even more resistant (2151).

James Craigie (CA) discovered that typhoid bacilli could be grouped according to sensitivity to certain phages (565).

Robert Joseph Huebner (US), Charles Pomerantz (US), William L. Jellison (US), and Peggy Stamps (US) isolated and named the etiological agent of rickettsialpox, Rickettsia akari, then determined the cycle of infection as mouse-mite-mouse, with man an occasional host (1316-1318).

Sydney Arthur Asdell (US) authored Patterns of Mammalian Reproduction in which he collected data bearing on reproductive behavior of wild as well as domestic mammals (77).

William Barry Wood, Jr. (US), Mary Ruth Smith (US), and Barbara Watson (US) studied the lungs of animals infected with encapsulated pneumococci early in the course of the disease, before antibody was produced. They discovered surface phagocytosis. On smooth surfaces the phagocytes were unable to engulf bacteria, whereas on rough surfaces they were often able to wedge the slippery bacteria into a corner where they could be phagocytized (3059, 3060).

Paul D. MacLean (US), Averill A. Liebow (US), and Arthur A. Rosenberg (US) first described Arcanobacterium hemolyticum infection in U.S. servicemen and peoples of the South Pacific suffering from sore throat (1749). Due to its resemblance to another type of bacteria, Corynebacterium, A. haemolyticum was initially classified as C. pyogenes subspecies hominus. Controversies regarding classification were resolved in 1982 when a new genus, Arcanobacterium (enigmatic bacterium) was created based on its peptidoglycan, fatty acid, and DNA characteristics.

Since its initial description, the spectrum of diseases caused by A. haemolyticum has been expanded to include sepsis and osteomyelitis.

Arthur Ernest Mourant (GB) discovered the Lewis blood group antigen in man. It is named for a Mrs. Lewis in which anti-Le was made (1926).

Eric A. Beet (GB), working in Northern Rhodesia, now Zimbabwe, suggested that sickle cell trait is caused by a mutant recessive gene, inherited in a Mendelian pattern (162-165).

James van Gundia Neel (US) proved that from the incidence of sickle cell disease and the trait in American Negro families that it is caused by a mutant recessive gene, inherited in a Mendelian pattern (1969).

Anthony Clifford Allison (GB-KE) performed an epidemiological study from which he concluded that the sickle cell trait protects carriers against malarial infection (37). This balance of advantage and disadvantage helped to explain why the sickle cell allele had been preserved in certain communities rather than being eliminated by natural selection.

Charles C. Macklin (CA) determined that there is no difference at all between positive and negative pressure inflation of the lung, as long as one is careful to reference airway and vascular pressures to the pleural pressure (1744).

Solbert Permutt (US), Jack B.L. Howell (GB), Donald F. Proctor (US), and Richard L. Riley (US) rediscovered Macklin’s findings (2073). In their companion paper they found that the pulmonary vascular bed could be functionally separated into two parts—alveolar and extra-alveolar vessels— that have opposite responses to lung inflation (1299).

Ulf Svante Hansson von Euler-Chelpin (SE) and Göran Liljestrand (SE) discovered what is now called the Euler-Liljestrand mechanism. This describes the connection between ventilation and blood circulation (perfusion) of the lung. If the ventilation in a part of the lung decreases it leads to local hypoxia. The local hypoxia leads to pulmonary vasoconstriction. This adaptive mechanism is beneficial, because it diminishes the amount of blood that passes the lung without being oxygenated (2835).

Robert J. Porcelli (US), Anna T. Viau (US), Margaret Demeny (US), Nosrat E. Naftchi (US) and Edward H. Bergofsky (US) reported that the molecular mechanism seems to be mediated by oxygen-sensitive potassium ion channels in the cell membrane of pulmonary smooth muscle. With a low partial pressure of oxygen, these channels are blocked, leading to the depolarization of the cell membrane. Calcium channels are activated and cause the influx of Ca2+ ions over the membrane and to the release of calcium from the endoplasmic reticulum. The rise of calcium concentration causes contraction of the blood vessels smooth muscle fibers and the resulting vasoconstriction (2119).

Kathleen Ethel Boorman (GB), Barbara Edith Dodd (GB), and John Freeman Loutit (GB) demonstrated the presence of autoantibodies on the erythrocytes of patients with acquired hemolytic anemia and the absence of rbc-bound antibodies in patients with congenital hemolytic anemia (255). This test to detect antibodies that had sensitized rbcs in vivo became known as the Direct Antiglobulin Test (DAT). A positive DAT is generally caused by the attachment of immunoglobulin (IgG, IgM, IgA) and / or components of complement (C3d, C3, C4 etc.) to the red cell surface.

Dwight Joyce Ingle (US) showed that characteristic damaging effects of stress are produced when adrenal steroids are supplied to adrenalectomized animals at a constant but not excessive rate of administration. He deduced that the role of the adrenal cortex in the stressed state appears to be a subtle “permissive” or supporting role rather than as the primary mediator of the stress reaction (1333).

Wallace Osgood Fenn (US), Hermann Rahn (DE-US), Arthur B. Otis (US), and Leigh E. Chadwick (US) developed the pressure-volume diagram of the lung and thorax. Hermann Rahn (DE-US) and William Osgood Fenn (US) wrote, A Graphical Analysis of the Respiratory Gas Exchange: The O2-CO2 Diagram in which they were able to represent all variables of the alveolar gas ventilation equations in diagrammatic form. With the O2-CO2 diagram they could represent all possible compositions of alveolar gas and the arterial blood under any specified set of conditions. Although F. Rohrer (?) preceded them on the pressure-volume diagram they conceived it independently, elaborated it further, and distilled into it some ten years of work and thought. It defined the limiting values for muscle forces and the corresponding volumes of gas and blood (886, 2154-2156). This work laid the foundation for respiratory mechanics.

Richard L. Riley (US) and André Frédéric Cournand (US) developed a three-compartment model of pulmonary gas exchange. This model was the standard for assessing ventilation-perfusion inequality in patients with lung disease until the introduction of the multiple inert gas elimination technique (2247, 2248).

WilliamE. Adams (US), in 1946, performed a lobectomy for carcinoma of the lung on Thomas Mann who authored the tuberculosissaga The Magic Mountain (1955).

Errol Ivor White (GB) discovered a fossil of Jamoytius kerwoodi in deposits of Silurian rock in Scotland. It is probably the most primitive chordate known and may throw some light on the early ancestry of vertebrates (2967).

1947

Robert Robinson (GB) was awarded the Nobel Prize in Chemistry for investigations on plant products of biological importance, especially the alkaloids.

Carl Ferdinand Cori (CZ-US) and Gerty Theresa Cori, née Radnitz (CZ-US), for their discovery of the course of the catalytic conversion of glycogen, and Bernardo Alberto Houssay (AR), for his discovery of the part played by the hormone of the anterior pituitary lobe in the metabolism of sugar, shared the Nobel Prize in physiology and medicine.

Immanuel Broser (DE) and Hartmut Kallman (DE) discovered that certain organic compounds called scintillators fluoresce when exposed to ionizing radiation. Each fluorescence event is proportional to a radioactive decay event, and the frequency of these events is directly proportional to the number of 14C atoms present in the sample (308). This discovery led to the development of liquid scintillation counters.

Norbert Weiner (US) conceived and developed a new kind of mathematics that he called cybernetics (negative feedback control). It was originally intended for the purpose of designing aiming devices for anti-aircraft guns and then later for guided missiles (2981). This concept quickly found acceptance in explaining the control of various biological phenomena. G. Evelyn Hutchinson (US) applied Weiner's cybernetics to Tansley's ecosystem leading to our modern concept of the ecosystem. Endocrinologists gradually realized that the language of feedback control provided an effective way of describing and thinking about endocrine interactions. Biochemists found that many metabolic pathways are controlled by feedback mechanisms.

Robert W. Dorner (US), Albert Kahn (US), and Sam G. Wildman (US) would declare this fraction I protein to be the enzyme ribulose-1, 5-biphosphate carboxylase-oxygenase (Rubisco), arguably the world’s most abundant and important single species of soluble protein (719). See, Weissbach, 1956.

Melvin Calvin (US), Andrew Alm Benson (US), and associates provided an important clue to the nature of the pathway from CO2 to hexose in photosynthetic organisms. They illuminated green algae in the presence of radioactive carbon dioxide (14CO2) for very short intervals (only a few seconds) and then quickly killed the cells, extracted them, and with the aid of chromatographic methods searched for those metabolites in which the labeled carbon was incorporated earliest. Melvin Calvin (US) and Andrew Alm Benson (US) determined that one of the compounds that became labeled very early in photosynthesis is 3-phosphoglyceric acid, a known intermediate of glycolysis; the carbon isotope was found predominantly in the carboxyl carbon atom. This carbon atom, which corresponds to the carboxyl carbon atom of pyruvate, is not labeled rapidly in animal tissues incubated with radioactive CO2 (182, 392-394).

Melvin Calvin (US) and Peter Massini (US) were the first to postulate that the carboxylation of a molecule of ribulose-1, 5-diphosphate (RuDP) produces two molecules of 3-phosphoglyceric acid (PGA) (395).

Alexander T. Wilson (NZ) and Melvin Calvin (US) gathered evidence that indeed ribulose 1,5-biphosphate is the first substance to react with carbon dioxide in the dark reactions of photosynthesis (391, 3024).

Arthur Weissbach (US), Pauline Z. Smyrniotis (US), and Bernard Leonard Horecker (US) were ableto show that with crude extracts from spinach leaves ribose 5-phosphatewas a unique substrate for the formation of phosphoglyceric acid,and they purified a kinase from spinach leaves that they usedto prepare the barium salt of ribulose 1,5-bisphosphate(RUDP) (2939).

Bernard Leonard Horecker (US), Arthur Weissbach (US), Pauline Z. Smyrniotis (US) and Jerard Hurwitz (US) isolated spinach phosphoribulokinase, performed the enzymatic synthesis of ribulose 1,5-diphosphate, and the enzymatic formation ofphosphoglyceric acid from ribulose diphosphate and carbon dioxide (1276, 1325, 2938). The Weissbach article in 1956 represents the first purification of the enzyme ribulose-1, 5-biphosphate carboxylase-oxygenase (Rubisco), arguably the world’s most abundant and important single species of soluble protein.

William A. Laing (NZ), William L. Ogren (US), and Richard H. Hageman (US) derived enzyme kinetic equations for a dual substrate enzyme and meticulously showed that the kinetic properties of the isolated Rubisco enzyme could explain the effects of both oxygen and temperature on photosynthesis and photorespiration (1562).

R. Weismann (CH) reported the H. Speich of Geigy Chemicals observed insect (housefly) resistance to dichloro-diphenyl-trichloro-ethane (DDT) or 2,2-di (4-chlorophenyl)-1,1,1-trichloroethane in northern Sweden—a mere five years after it was first used there (2935).

John Ehrlich (US), Quentin R. Bartz (US), Robert M. Smith (US), Dwight A. Joslyn (US), and Paul Rufus Burkholder (US) isolated the antibiotic chloromycetin (Chloramphenicol) from the actinomycete Streptomyces venezuelae, recovered from soil obtained near Caracas, Venezuela (796, 797). Chloramphenicol blocks the peptidyl transferase reaction on ribosomes of prokaryotes only. To this point in time chemists were convinced that nature could neither chlorinate nor nitrate its products. Chloramphenicol proved them wrong on both counts.

Otto Fritz Meyerhof (DE-US) and Peter Oesper (US) provided furtherproof that during glycolysis a diphosphoglyceric aldehyde intermediate does notexist. They also altered the equation for this step of glycolysisto reflect the fact that the reduction of cozymase is accompaniedby the formation of an H+ ion (1881).

James Frederick Bonner (US), Ru-Chih Huang (US), and Nirmala Maheshwari (US) discovered the synthesis of RNA from DNA in plants. They found that RNA transcription is inhibited by histones (253, 1306).

Ru-chih C. Huang (US) and James Frederick Bonner (US) reported that histones influence the ability of DNA to function as primer for RNA synthesis in vitro (1305).

James Frederick Bonner (US), Ru-chih C. Huang (US), and Ray Guilden (US) provided experimental evidence that the inhibition of RNA synthesis by histones is specific (252). This was experimental confirmation of the hypothesis by Stedman & Stedman in 1947.

Derek Michael Phillips Phillips (GB) discovered that the amino-terminal tails of the four histones (H2A, H2B, H3, and H4) are post-transcriptionally modified by the addition of an acetyl group to the epsilon amino group of specific lysine side chains (2091).

Vincent George Allfrey (US), Robert D. Faulkner (US), and Alfred Ezra Mirsky (US) suggested that such a seemingly minor modification to histones could be involved in the control of gene expression via its “effect on the capacity of the histones to inhibit ribonucleic acid synthesis” (36).

John Masson Gulland (GB) reported that undegraded calf thymus DNA contains large polynucleotide chains held together by hydrogen bonds (1100).

André Félix Boivin (FR) and Roger Vendrely (FR) were the first to express, in print, that DNA makes RNA makes protein (247).

Michael Doudoroff (RU-US), Horace Albert Barker (US), and William Zev Hassid (RU-GB-US) studied the action of bacterial sucrose phosphorylase in what represents an outstanding early example of the use of radioisotopes for the study of enzyme mechanisms (725).

Theodor Bücher (DE) discovered that during glycolysis when glyceraldehyde-3-phosphate is oxidized the immediate product is 1,3-diphosphoglycerate, which donates its phosphoryl group to ADP in the presence of 3-phosphoglycerate kinase (333).

Milislav L. Demerec (Yugoslavian -US) explained how bacteria can mutate to resist higher and higher concentrations of an antibiotic. Resistance to penicillin is a step-wise phenomenon due to mutants at three different genes being selected as the concentration of antibiotic rises. The probability of all three mutations appearing in the same cell is 10-7 X 10-7 X 10-7 =10-21. Mutation to various levels of streptomycin resistance occurs even at low levels of the antibiotic.

These discoveries taught lessons for the clinical application of antibiotics such as penicillin and streptomycin. If a patient afflicted with a bacterial infection is to be treated with penicillin, the physician must employ the highest possible concentration of the drug at the very outset; for in that way the chance that all the pathogenic bacteria are killed is maximized, and the chance that high-level resistant mutants are selected is minimized. The avoidance of stepwise mutants is less important in streptomycin treatment, since mutants with high resistance to that drug are selected even in the presence of low concentrations, and little can be done to avoid their appearance. The surest way to avoid the appearance of drug-resistant strains is to administer simultaneously two or more kinds of antibiotics, since the chance that a multiple-resistant mutant will appear is given by the product of the individual mutation rates (645).

John Franklin Enders (US) succeeded in transmitting primary atypical pneumonia to human volunteers by means of filtered secretions from the respiratory tract. This strongly suggested a viral etiology for this disease (835).

Edgar G. Anderson (US) and William Lacy Brown (US) published landmark monographs on the two ancestral maize types (Southern Dents and Northern Flints) that, when hybridized, gave rise to the North American race (Corn Belt Dent). Corn Belt Dent is the genetic foundation for all hybrid maize of the temperate zones (317-319).

Frederick E. J. Fry (CA) developed a model for the way fish respond to their physical and chemical environment. He divided all environmental effects on fish into five classes, controlling, limiting, lethal, masking and directive, increasing understanding of how environmental factors interact to affect performance of individual fish and their populations at any given time (968).

Min Chueh Chang (CN-US) disproved the need for large amounts of hyaluronidase at the site of fertilization and the claim that phosphorylated hesperidin, a hyaluronidase inhibitor, had man antifertility action when given orally (437, 438).

Frederick O. MacCallum (GB), using human volunteers, differentiated hepatitis A, which is spread by contaminated food and water, from hepatitis B, which is spread by blood (1739).

Robert John Walsh (GB) and Carmel M. Montgomery (GB) discovered the Ss blood group antigen (2890).

Paul A. Owren (NO) discovered the activated form of factor V (Va) of the blood clotting mechanism (2019, 2020). This factor has also been called proaccelerin.

Paul A. Owren (NO) described a hemorrhagic disease in a young womanlacking a plasma protein that was called proaccelerin. Thisdisease is referred to as parahemophilia (factor V deficiency) (2021).

Thomas Francis, Jr. (US) discovered a non-antibody serum factor which prevents the agglutination of erythrocytes by myxoviruses. It is referred to as the Francis’ inhibitor (equivalent to alpha-inhibitor) (939).

C.M. Chu (GB) observed a similar factor, now called Chu’s inhibitor (equivalent to beta-inhibitor) (461).

Robert B. Howard (US) and Cecil James Watson (US) discovered that patients with evolving cirrhosis of the liver often have an antecedent transient episode of jaundice (1298).

Aaron Bunsen Lerner (US) and Cecil James Watson (US) discovered cryoglobulins in the sera of some patients with purpura (1630).

Isaac Berenblum (IL) and Philippe Shubik (GB) discovered that cancer caused by chemicals involves two distinct steps, initiation and promotion. The first step, initiation, was theorized to be a rapid mutational effect on the cellular DNA. The second step, promotion, was believed to be caused by a promoting agent, which altered cellular metabolism, growth, and transport (185, 186).

Robert James Morton (US), Malcolm McCallum Hargraves (US), and Helen Robinson (US) discovered a mature neutrophilic polymorphonuclear leucocyte containing the phagocytosed nucleus of another cell and recognized it as a diagnostic aid in acutedisseminatedlupus erythematosus (1158, 1923). The L.E. (lupus erythematosus) cell discovery was the first clear sign that systemic lupus erythematosus could be an autoimmune disease, i.e., Hargraves’ cells.

Thomas Holmes Sellers (GB), in 1947, performed the first successful pulmonary valvulotomy. A systemic pulmonary artery shunt was planned on the left side, but the attempt was abandoned in this patient with severe tetralogy of Fallot and advanced bilateral pulmonary tuberculosis. The pericardium was opened. Dr. Sellers could feel the stenotic valve each time it pushed through the pulmonary trunk during ventricular systole. Sellers used a tenotomy knife, which he passed through the right ventricle to perform the valvulotomy. The patient made a good recovery and was markedly improved (2436).

Jean-Pierre Soulier (FR) and Jean Gueguen (FR) discovered the anticoagulant phenylidane-dione and the first successful preparation of a therapeutic fraction from blood to treat factor IX and prothrombin complex deficiencies (2571).

Alexander Brunschwig (US), in 1946, performed a total pelvic exenteration (surgical removal of the pelvic organs and nearby structures) on a patient with recurrent carcinoma of the cervix (328, 329).

Gerhardt von Bonin (US) and Percival Bailey (US) were the first to define with precision the cytoarchitecture of the human brain cortex (106, 2825).

Jens Christian Clausen (DK-US), David D. Keck (US), and William M. Heisey (US) used variation in the sticky cinquefoil (Potentilla glandulosa) and the yarrow (Achillea lanulosa) to perform the first documented experimental analysis of genetic differentiation in adjacent populations. During these experiments they introduced transplant experiments as an appropriate technique for distinguishing genetic from environmental effects (478, 479). These experiments clarified for certain species and under certain condition the question of heredity versus environment.

Edward Smith Deevey, Jr. (US) introduced the concept of the life table to ecology (639).

Reginald Claude Sprigg (AU) discovered Precambrian metazoan fossils in the Pound Quartzite at Ediacara Hills and in the Flinders Ranges of South Australia (2583, 2584). This represents the dawn of visible life forms.

Edwin H. Colbert (US), curator of the American Museum of Natural History, found a massive quarry of Coelophysis dinosaurs in New Mexico and concluded from their skeletons that these Triassic dinosaurs were swift runners with a bird-like posture (501).

21. Albright F, Aub JC, Bauer W. 1934b. Hyperparathyroidism: a common and polymorphic condition as illustrated by seventeen proven cases from one clinic. Journal of the American Medical Association 102: 1276-87

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